Cell autonomous sex identity

The concept of cell autonomous sex identity (CASI) emerged as a challenge to the traditional understanding of sexual differentiation, which largely centered around the role of gonadal hormones in directing the development of sex-specific traits. Early research on sex determination systems focused heavily on the influence of hormonal signaling, particularly in mammals, where the testes and ovaries are known to orchestrate a cascade of changes in both primary and secondary sexual characteristics.{{Cite journal |last1=Blecher |first1=Stan R. |last2=Erickson |first2=Robert P. |date=2007 |title=Genetics of sexual development: A new paradigm |url=https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.32037 |journal=American Journal of Medical Genetics Part A |language=en |volume=143A |issue=24 |pages=3054–3068 |doi=10.1002/ajmg.a.32037 |pmid=18000910 |issn=1552-4833}}{{Cite journal |last1=Morrish |first1=B. C. |last2=Sinclair |first2=A. H. |date=2002-10-01 |title=Vertebrate sex determination: many means to an end |url=https://rep.bioscientifica.com/view/journals/rep/124/4/447.xml |journal=Reproduction |language=en-US |volume=124 |issue=4 |pages=447–457 |doi=10.1530/rep.0.1240447 |pmid=12361462 |issn=1741-7899}}{{Cite journal |last1=O. |first1=Wai-Sum |last2=Short |first2=R. V. |last3=Renfree |first3=Marilyn B. |last4=Shaw |first4=G. |date=1988-02-25 |title=Primary genetic control of somatic sexual differentiation in a mammal |url=https://www.nature.com/articles/331716a0 |journal=Nature |language=en |volume=331 |issue=6158 |pages=716–717 |doi=10.1038/331716a0 |pmid=3344046 |bibcode=1988Natur.331..716W |issn=1476-4687}}

The first indications that sex identity could be cell-autonomous rather than entirely hormone-driven arose from studies in non-mammalian species, particularly birds and insects. In the mid-20th century, researchers investigating sexual dimorphism in avian species observed that male and female cells could exhibit distinct characteristics even when exposed to the same hormonal environment. This led to the hypothesis that sex determination might occur at the cellular level in some cases, independent of systemic hormonal control.

The field gained significant traction in the 21st century with advancements in genetic and molecular biology. Landmark studies in chickens demonstrated that individual cells in somatic tissues could retain their sex identity regardless of the hormonal milieu, providing compelling evidence for CASI. This finding contrasted sharply with mammalian models, where hormonal influences were thought to dominate sexual differentiation.{{Cite journal |last=Smith |first=Craig A. |date=2010-12-01 |title=Sex determination in birds: a review |url=https://www.tandfonline.com/doi/abs/10.1071/MU10030 |journal=Emu - Austral Ornithology |volume=110 |issue=4 |pages=364–377 |doi=10.1071/mu10030 |issn=0158-4197}}

Further research expanded the scope of CASI to other species, such as insects and fish, revealing diverse mechanisms by which sex chromosomes and gene expression patterns could directly influence cellular phenotypes. These discoveries underscored the evolutionary diversity in sex determination processes and highlighted the importance of CASI in understanding sexual dimorphism across the animal kingdom.{{Cite journal |last1=Raymond |first1=Christopher S. |last2=Kettlewell |first2=Jae R. |last3=Hirsch |first3=Betsy |last4=Bardwell |first4=Vivian J. |last5=Zarkower |first5=David |date=1999-11-15 |title=Expression of Dmrt1 in the Genital Ridge of Mouse and Chicken Embryos Suggests a Role in Vertebrate Sexual Development |url=https://linkinghub.elsevier.com/retrieve/pii/S0012160699994617 |journal=Developmental Biology |volume=215 |issue=2 |pages=208–220 |doi=10.1006/dbio.1999.9461 |pmid=10545231 |issn=0012-1606}}

On-going research into exploring the implications of CASI for evolution, health and disease continue. The historical shift from hormone-centric models to a more nuanced understanding that includes cell-autonomous mechanisms marks a significant paradigm change in the study of sexual differentiation.{{Cite journal |last1=Davies |first1=William |last2=Wilkinson |first2=Lawrence S. |date=2006-12-18 |title=It is not all hormones: Alternative explanations for sexual differentiation of the brain |url=https://linkinghub.elsevier.com/retrieve/pii/S000689930602854X |journal=Brain Research |series=Sex, Genes and Steroids |volume=1126 |issue=1 |pages=36–45 |doi=10.1016/j.brainres.2006.09.105 |pmid=17101121 |issn=0006-8993}}{{Cite journal |last1=Bowles |first1=Josephine |last2=Koopman |first2=Peter |date=2010-06-01 |title=Sex determination in mammalian germ cells: extrinsic versus intrinsic factors |url=https://rep.bioscientifica.com/view/journals/rep/139/6/943.xml |journal=Reproduction |language=en-US |volume=139 |issue=6 |pages=943–958 |doi=10.1530/REP-10-0075 |pmid=20395427 |issn=1741-7899}}

Cell autonomous sex identity arises from the intrinsic properties of individual cells, determined by genetic and epigenetic factors encoded by their sex chromosomes. Unlike hormone-driven sex differentiation, where external chemical signals guide the development of sexual traits, CASI relies on the direct expression of genes and regulatory networks that are inherently linked to a cell's chromosomal sex.{{Citation |last=Arnold |first=Arthur P. |title=Chapter Ten - Rethinking sex determination of non-gonadal tissues |date=2019-01-01 |journal=Current Topics in Developmental Biology |volume=134 |pages=289–315 |editor-last=Capel |editor-first=Blanche |series=Sex Determination in Vertebrates |publisher=Academic Press |doi=10.1016/bs.ctdb.2019.01.003 |pmc=7485614 |pmid=30999979}}{{Cite journal |last=Arnold |first=Arthur P. |date=2012-02-01 |title=The end of gonad-centric sex determination in mammals |journal=Trends in Genetics |language=English |volume=28 |issue=2 |pages=55–61 |doi=10.1016/j.tig.2011.10.004 |issn=0168-9525 |pmc=3268825 |pmid=22078126}}

At the core of CASI is the differential expression of genes located on the sex chromosomes (e.g., Z and W in birds, X and Y in mammals). In organisms where CASI has been observed, the presence of these sex chromosomes directly influences the transcriptional landscape of individual cells, leading to sex-specific cellular characteristics. For example, in birds, studies have shown that male (ZZ) and female (ZW) cells exhibit distinct gene expression profiles even when exposed to identical hormonal environments.{{Cite journal |last1=Burgoyne |first1=Paul S. |last2=Arnold |first2=Arthur P. |date=2016-12-13 |title=A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues |journal=Biology of Sex Differences |volume=7 |issue=1 |pages=68 |doi=10.1186/s13293-016-0115-5 |doi-access=free |issn=2042-6410 |pmc=5154145 |pmid=27999654}}

Genes located on sex chromosomes, such as DMRT1 in birds and TRA-1 in some insects, play crucial roles in establishing cell-autonomous sex identity. These genes are often expressed in a sex-specific manner, driving divergent developmental pathways at the cellular level.{{Cite journal |last1=Burgoyne |first1=Paul S. |last2=Buehr |first2=Mia |last3=Koopman |first3=Peter |last4=Rossant |first4=Janet |last5=Mclaren |first5=Anne |date=1988-02-01 |title=Cell-autonomous action of the testis-determining gene: Sertoli cells are exclusively XY in XX ↔XY chimaeric mouse testes |url=https://journals.biologists.com/dev/article/102/2/443/35912/Cell-autonomous-action-of-the-testis-determining |journal=Development |volume=102 |issue=2 |pages=443–450 |doi=10.1242/dev.102.2.443 |pmid=3166423 |issn=0950-1991}}{{Cite journal |last1=Capel |first1=Blanche |last2=Albrecht |first2=Kenneth H |last3=Washburn |first3=Linda L |last4=Eicher |first4=Eva M |date=1999-06-01 |title=Migration of mesonephric cells into the mammalian gonad depends on Sry |url=https://linkinghub.elsevier.com/retrieve/pii/S0925477399000477 |journal=Mechanisms of Development |volume=84 |issue=1 |pages=127–131 |doi=10.1016/S0925-4773(99)00047-7 |pmid=10473126 |issn=0925-4773}}{{Cite journal |last1=De Santa Barbara |first1=Pascal |last2=Moniot |first2=Brigitte |last3=Poulat |first3=Francis |last4=Berta |first4=Philippe |date=2000-03-01 |title=Expression and subcellular localization of SF-1, SOX9, WT1, and AMH proteins during early human testicular development |url=https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0177(200003)217:33.0.CO;2-P |journal=Developmental Dynamics |language=en |volume=217 |issue=3 |pages=293–298 |doi=10.1002/(SICI)1097-0177(200003)217:3<293::AID-DVDY7>3.0.CO;2-P |pmid=10741423 |issn=1058-8388}}

Epigenetic modifications, such as DNA methylation and histone modifications, contribute to the regulation of sex-specific gene expression. In some cases, these modifications help maintain the cellular memory of sex identity throughout an organism's life.{{Cite journal |last1=Heard |first1=Edith |last2=Disteche |first2=Christine M. |date=2006-07-15 |title=Dosage compensation in mammals: fine-tuning the expression of the X chromosome |url=https://genesdev.cshlp.org/content/20/14/1848 |journal=Genes & Development |language=en |volume=20 |issue=14 |pages=1848–1867 |doi=10.1101/gad.1422906 |issn=0890-9369 |pmid=16847345|doi-access=free }}{{Cite journal |last1=Chow |first1=Jennifer |last2=Heard |first2=Edith |date=2009-06-01 |title=X inactivation and the complexities of silencing a sex chromosome |url=https://linkinghub.elsevier.com/retrieve/pii/S0955067409000982 |journal=Current Opinion in Cell Biology |series=Nucleus and gene expression |volume=21 |issue=3 |pages=359–366 |doi=10.1016/j.ceb.2009.04.012 |pmid=19477626 |issn=0955-0674}}{{Cite journal |last1=Payer |first1=Bernhard |last2=Lee |first2=Jeannie T. |last3=Namekawa |first3=Satoshi H. |date=2011-08-01 |title=X-inactivation and X-reactivation: epigenetic hallmarks of mammalian reproduction and pluripotent stem cells |journal=Human Genetics |language=en |volume=130 |issue=2 |pages=265–280 |doi=10.1007/s00439-011-1024-7 |issn=1432-1203 |pmc=3744832 |pmid=21667284}}{{Cite journal |last1=Kuroki |first1=Shunsuke |last2=Tachibana |first2=Makoto |date=2018-06-15 |title=Epigenetic regulation of mammalian sex determination |url=https://linkinghub.elsevier.com/retrieve/pii/S0303720717306342 |journal=Molecular and Cellular Endocrinology |series=The impact of new technologies in our understanding of gonadal formation and function |volume=468 |pages=31–38 |doi=10.1016/j.mce.2017.12.006 |pmid=29248548 |issn=0303-7207}}{{Citation |last1=Miller |first1=Jaime L. |title=The Role of DNA Methylation and Histone Modifications in Transcriptional Regulation in Humans |date=2013 |work=Epigenetics: Development and Disease |pages=289–317 |editor-last=Kundu |editor-first=Tapas K. |place=Dordrecht |publisher=Springer Netherlands |language=en |doi=10.1007/978-94-007-4525-4_13 |isbn=978-94-007-4525-4 |pmc=6611551 |pmid=23150256 |last2=Grant |first2=Patrick A.|volume=61 }}

Intrinsic signaling pathways within the cell can reinforce sex-specific gene expression and cellular phenotypes. These pathways act independently of systemic hormonal influences, highlighting the autonomy of CASI.{{Cite journal |last=Kauffman |first=A. S. |date=2010 |title=Gonadal and Nongonadal Regulation of Sex Differences in Hypothalamic Kiss1 Neurones |journal=Journal of Neuroendocrinology |language=en |volume=22 |issue=7 |pages=682–691 |doi=10.1111/j.1365-2826.2010.02030.x |issn=1365-2826 |pmc=3096441 |pmid=20492362}}{{Cite journal |last1=Kammel |first1=Laura G. |last2=Correa |first2=Stephanie M. |date=2020 |title=Selective sexual differentiation of neurone populations may contribute to sex-specific outputs of the ventromedial nucleus of the hypothalamus |journal=Journal of Neuroendocrinology |language=en |volume=32 |issue=1 |pages=e12801 |doi=10.1111/jne.12801 |issn=1365-2826 |pmc=6982598 |pmid=31605642}}{{Cite journal |last1=Manolakou |first1=Panagiota |last2=Lavranos |first2=Giagkos |last3=Angelopoulou |first3=Roxani |date=2006-11-13 |title=Molecular patterns of sex determination in the animal kingdom: a comparative study of the biology of reproduction |journal=Reproductive Biology and Endocrinology |volume=4 |issue=1 |pages=59 |doi=10.1186/1477-7827-4-59 |doi-access=free |issn=1477-7827 |pmc=1660543 |pmid=17101057}}{{Citation |last1=Beukeboom |first1=Leo W. |title=Molecular mechanisms of sex determination |date=2014-06-12 |work=The Evolution of Sex Determination |pages=0 |editor-last=Beukeboom |editor-first=Leo W. |url=https://academic.oup.com/book/25435/chapter-abstract/192588922?redirectedFrom=fulltext |access-date=2025-01-18 |publisher=Oxford University Press |doi=10.1093/acprof:oso/9780199657148.003.0003 |isbn=978-0-19-965714-8 |last2=Perrin |first2=Nicolas |editor2-last=Perrin |editor2-first=Nicolas}}

While CASI primarily relies on sex chromosome-linked factors, interactions with autosomal genes also contribute to the establishment and maintenance of sex-specific traits. For example, some autosomal genes are regulated by sex-specific transcription factors encoded on the sex chromosomes.{{Cite journal |last1=Ayers |first1=Katie L. |last2=Davidson |first2=Nadia M. |last3=Demiyah |first3=Diana |last4=Roeszler |first4=Kelly N. |last5=Grützner |first5=Frank |last6=Sinclair |first6=Andrew H. |last7=Oshlack |first7=Alicia |last8=Smith |first8=Craig A. |date=2013-03-25 |title=RNA sequencing reveals sexually dimorphic gene expression before gonadal differentiation in chicken and allows comprehensive annotation of the W-chromosome |journal=Genome Biology |volume=14 |issue=3 |pages=R26 |doi=10.1186/gb-2013-14-3-r26 |doi-access=free |issn=1474-760X |pmc=4053838 |pmid=23531366}}{{Cite journal |last1=Oliva |first1=Meritxell |last2=Muñoz-Aguirre |first2=Manuel |last3=Kim-Hellmuth |first3=Sarah |last4=Wucher |first4=Valentin |last5=Gewirtz |first5=Ariel D. H. |last6=Cotter |first6=Daniel J. |last7=Parsana |first7=Princy |last8=Kasela |first8=Silva |last9=Balliu |first9=Brunilda |last10=Viñuela |first10=Ana |last11=Castel |first11=Stephane E. |last12=Mohammadi |first12=Pejman |last13=Aguet |first13=François |last14=Zou |first14=Yuxin |last15=Khramtsova |first15=Ekaterina A. |date=2020-09-11 |title=The impact of sex on gene expression across human tissues |journal=Science |volume=369 |issue=6509 |pages=eaba3066 |doi=10.1126/science.aba3066 |pmc=8136152 |pmid=32913072}}{{Cite journal |last1=Gayen |first1=Srimonta |last2=Maclary |first2=Emily |last3=Hinten |first3=Michael |last4=Kalantry |first4=Sundeep |date=2016-01-19 |title=Sex-specific silencing of X-linked genes by Xist RNA |journal=Proceedings of the National Academy of Sciences |volume=113 |issue=3 |pages=E309–E318 |doi=10.1073/pnas.1515971113 |doi-access=free |pmc=4725534 |pmid=26739568|bibcode=2016PNAS..113E.309G }}

• Avian Somatic Cells: Studies in birds, such as chickens, have demonstrated that male and female somatic cells can maintain their sexual identity in mixed-sex chimeras, providing direct evidence of CASI.{{Cite journal |last1=Clinton |first1=Michael |last2=Zhao |first2=Debiao |date=2023-02-16 |title=Avian Sex Determination: A Chicken and Egg Conundrum |url=https://karger.com/sxd/article/17/2-3/120/835808/Avian-Sex-Determination-A-Chicken-and-Egg |journal=Sexual Development |volume=17 |issue=2–3 |pages=120–133 |doi=10.1159/000529754 |issn=1661-5425 |pmc=10659007 |pmid=36796340}}{{Cite journal |last1=Ioannidis |first1=Jason |last2=Taylor |first2=Gunes |last3=Zhao |first3=Debiao |last4=Liu |first4=Long |last5=Idoko-Akoh |first5=Alewo |last6=Gong |first6=Daoqing |last7=Lovell-Badge |first7=Robin |last8=Guioli |first8=Silvana |last9=McGrew |first9=Mike J. |last10=Clinton |first10=Michael |date=2021-03-09 |title=Primary sex determination in birds depends on DMRT1 dosage, but gonadal sex does not determine adult secondary sex characteristics |journal=Proceedings of the National Academy of Sciences |volume=118 |issue=10 |pages=e2020909118 |doi=10.1073/pnas.2020909118 |doi-access=free |pmc=7958228 |pmid=33658372|bibcode=2021PNAS..11820909I }}{{Cite journal |last1=Lengyel |first1=Kamila |last2=Rudra |first2=Mekhla |last3=Berghof |first3=Tom V. L. |last4=Leitão |first4=Albertine |last5=Frankl-Vilches |first5=Carolina |last6=Dittrich |first6=Falk |last7=Duda |first7=Denise |last8=Klinger |first8=Romina |last9=Schleibinger |first9=Sabrina |last10=Sid |first10=Hicham |last11=Trost |first11=Lisa |last12=Vikkula |first12=Hanna |last13=Schusser |first13=Benjamin |last14=Gahr |first14=Manfred |date=2024-10-17 |title=Unveiling the critical role of androgen receptor signaling in avian sexual development |journal=Nature Communications |language=en |volume=15 |issue=1 |pages=8970 |doi=10.1038/s41467-024-52989-w |issn=2041-1723 |pmc=11487053 |pmid=39419984|bibcode=2024NatCo..15.8970L }}
• Drosophila (Fruit Flies): Insects like fruit flies exhibit CASI in the differentiation of somatic tissues, where sex-specific transcription factors directly influence cellular development.{{Cite journal |last1=Steinmann-Zwicky |first1=Monica |last2=Schmid |first2=Helen |last3=Nöthiger |first3=Rolf |date=1989-04-07 |title=Cell-autonomous and inductive signals can determine the sex of the germ line of Drosophila by regulating the gene Sxl |url=https://linkinghub.elsevier.com/retrieve/pii/0092867489901815 |journal=Cell |language=English |volume=57 |issue=1 |pages=157–166 |doi=10.1016/0092-8674(89)90181-5 |issn=0092-8674 |pmid=2702687}}{{Cite journal |last1=Chang |first1=Peter L |last2=Dunham |first2=Joseph P |last3=Nuzhdin |first3=Sergey V |last4=Arbeitman |first4=Michelle N |date=December 2011 |title=Somatic sex-specific transcriptome differences in Drosophila revealed by whole transcriptome sequencing |journal=BMC Genomics |language=en |volume=12 |issue=1 |page=364 |doi=10.1186/1471-2164-12-364 |doi-access=free |issn=1471-2164 |pmc=3152543 |pmid=21756339}}{{Cite journal |last1=Dauwalder |first1=Brigitte |last2=Tsujimoto |first2=Susan |last3=Moss |first3=Jason |last4=Mattox |first4=William |date=2002-11-15 |title=The Drosophila takeout gene is regulated by the somatic sex-determination pathway and affects male courtship behavior |url=https://genesdev.cshlp.org/content/16/22/2879 |journal=Genes & Development |language=en |volume=16 |issue=22 |pages=2879–2892 |doi=10.1101/gad.1010302 |issn=0890-9369 |pmc=187483 |pmid=12435630}}{{Cite journal |last1=Arbeitman |first1=Michelle N. |last2=Fleming |first2=Alice A. |last3=Siegal |first3=Mark L. |last4=Null |first4=Brian H. |last5=Baker |first5=Bruce S. |date=2004-05-01 |title=A genomic analysis of Drosophila somatic sexual differentiation and its regulation |url=https://journals.biologists.com/dev/article/131/9/2007/42886/A-genomic-analysis-of-Drosophila-somatic-sexual |journal=Development |volume=131 |issue=9 |pages=2007–2021 |doi=10.1242/dev.01077 |pmid=15056610 |issn=0950-1991}}
• Fish Gonads: CASI has also been observed in fish species where gonadal cells retain their sex identity independent of external hormonal cues.{{Cite journal |last1=Kurokawa |first1=Hiromi |last2=Saito |first2=Daisuke |last3=Nakamura |first3=Shuhei |last4=Katoh-Fukui |first4=Yuko |last5=Ohta |first5=Kohei |last6=Baba |first6=Takashi |last7=Morohashi |first7=Ken-ichiro |last8=Tanaka |first8=Minoru |date=2007-10-23 |title=Germ cells are essential for sexual dimorphism in the medaka gonad |journal=Proceedings of the National Academy of Sciences |volume=104 |issue=43 |pages=16958–16963 |doi=10.1073/pnas.0609932104 |doi-access=free |pmc=2040408 |pmid=17940041|bibcode=2007PNAS..10416958K }}{{Cite journal |last1=Rajendiran |first1=Preetha |last2=Jaafar |first2=Faizul |last3=Kar |first3=Sonika |last4=Sudhakumari |first4=Chenichery |last5=Senthilkumaran |first5=Balasubramanian |last6=Parhar |first6=Ishwar S. |date=2021-09-27 |title=Sex Determination and Differentiation in Teleost: Roles of Genetics, Environment, and Brain |journal=Biology |language=en |volume=10 |issue=10 |pages=973 |doi=10.3390/biology10100973 |doi-access=free |issn=2079-7737 |pmc=8533387 |pmid=34681072}}{{Cite journal |last1=Aharon |first1=Devora |last2=Marlow |first2=Florence L. |date=2021-12-22 |title=Sexual determination in zebrafish |journal=Cellular and Molecular Life Sciences |language=en |volume=79 |issue=1 |pages=8 |doi=10.1007/s00018-021-04066-4 |issn=1420-9071 |pmc=11072476 |pmid=34936027}}

The mechanisms underlying CASI highlight the diversity and complexity of sex determination processes across species. These insights challenge the traditional hormone-centric view of sexual differentiation and emphasize the importance of understanding cell-intrinsic factors in shaping sex-specific development.

Research on cell autonomous sex identity has leveraged various model organisms to uncover the genetic, cellular, and developmental mechanisms underlying sex-specific traits. These studies have provided valuable insights into how CASI operates across different taxa and contributed to a broader understanding of sex determination and differentiation.

Birds, particularly chickens (Gallus gallus), have been instrumental in studying CASI. Unlike mammals, where gonadal hormones dominate sex differentiation, avian somatic cells exhibit intrinsic sex identity. Studies using mixed-sex chimeric chickens demonstrated that male (ZZ) and female (ZW) cells maintain their distinct sexual identity even when transplanted into tissues of the opposite sex. The DMRT1 gene, located on the Z chromosome, has been identified as a key regulator of CASI in birds. Its dosage-dependent expression in males plays a critical role in driving male-specific development.{{Cite journal |last1=Guioli |first1=Silvana |last2=Zhao |first2=Debiao |last3=Nandi |first3=Sunil |last4=Clinton |first4=Michael |last5=Lovell-Badge |first5=Robin |date=2020-02-25 |title=Oestrogen in the chick embryo can induce chromosomally male ZZ left gonad epithelial cells to form an ovarian cortex that can support oogenesis |journal=Development |volume=147 |issue=4 |pages=dev181693 |doi=10.1242/dev.181693 |issn=0950-1991 |pmc=7055392 |pmid=32001442}}{{Cite journal |last1=Denham |first1=Scott |last2=Betterton |first2=Victoria |last3=Ioannidis |first3=Jason |last4=Lee |first4=Patricia |last5=Zhao |first5=Debiao |last6=Simpson |first6=Joanna |last7=Caughey |first7=Sarah |last8=Dunn |first8=Ian |last9=Clinton |first9=Mike |last10=Wilson |first10=Peter |last11=Homer |first11=Natalie |date=2021-10-18 |title=A Novel LC-MS/MS Method for the Simultaneous Detection of Multiple Steroids in Plasma and Tissue Lysates, used to verify Cell Autonomous Sex Identity in birds |url=https://www.endocrine-abstracts.org/ea/0077/ea0077lb57 |journal=Endocrine Abstracts |language=en |publisher=Bioscientifica |volume=77 |doi=10.1530/endoabs.77.LB57}}{{Cite journal |last1=Cheng |first1=Yu |last2=Zhang |first2=Zhen |last3=Zhang |first3=Guixin |last4=Chen |first4=Ligen |last5=Zeng |first5=Cuiping |last6=Liu |first6=Xiaoli |last7=Feng |first7=Yanping |date=2022-10-29 |title=The Male-Biased Expression of miR-2954 Is Involved in the Male Pathway of Chicken Sex Differentiation |journal=Cells |language=en |volume=12 |issue=1 |pages=4 |doi=10.3390/cells12010004 |doi-access=free |issn=2073-4409 |pmc=9818168 |pmid=36611798}}

In the fruit fly (Drosophila melanogaster), CASI is evident in the development of sex-specific somatic tissues, such as bristles and reproductive structures. The sex determination pathway in Drosophila is governed by the Sex-lethal (Sxl) gene, which initiates a cascade of transcriptional events leading to sex-specific alternative splicing of downstream genes like doublesex (dsx). This pathway operates independently in each cell, demonstrating the cell-autonomous nature of sex determination in this species.{{Cite journal |last=Steinmann-Zwicky |first=Monica |date=1994-03-01 |title=Sex determination of the Drosophila germ line: tra and dsx control somatic inductive signals |url=https://journals.biologists.com/dev/article/120/3/707/38219/Sex-determination-of-the-Drosophila-germ-line-tra |journal=Development |volume=120 |issue=3 |pages=707–716 |doi=10.1242/dev.120.3.707 |pmid=8162863 |issn=0950-1991}}{{Citation |last1=Camara |first1=Nicole |title=Chapter 3 The Creation of Sexual Dimorphism in the Drosophila Soma |date=2008-01-01 |journal=Current Topics in Developmental Biology |volume=83 |pages=65–107 |url=https://linkinghub.elsevier.com/retrieve/pii/S0070215308004031 |access-date=2025-01-18 |series=Sex Determination and Sexual Development |publisher=Academic Press |doi=10.1016/s0070-2153(08)00403-1 |last2=Whitworth |first2=Cale |last3=Van Doren |first3=Mark|pmid=19118664 |isbn=978-0-12-374496-8 }}{{Cite journal |last1=Hérault |first1=Chloé |last2=Pihl |first2=Thomas |last3=Hudry |first3=Bruno |date=2024-08-13 |title=Cellular sex throughout the organism underlies somatic sexual differentiation |journal=Nature Communications |language=en |volume=15 |issue=1 |pages=6925 |doi=10.1038/s41467-024-51228-6 |issn=2041-1723 |pmc=11322332 |pmid=39138201|bibcode=2024NatCo..15.6925H }}{{Cite journal |last1=Chang |first1=Peter L. |last2=Dunham |first2=Joseph P. |last3=Nuzhdin |first3=Sergey V. |last4=Arbeitman |first4=Michelle N. |date=2011-07-14 |title=Somatic sex-specific transcriptome differences in Drosophila revealed by whole transcriptome sequencing |journal=BMC Genomics |volume=12 |issue=1 |pages=364 |doi=10.1186/1471-2164-12-364 |doi-access=free |issn=1471-2164 |pmc=3152543 |pmid=21756339}}

Zebrafish (Danio rerio), a widely used vertebrate model, have also been studied for CASI, particularly in the context of gonadal development. While zebrafish lack sex chromosomes, sex-specific gene expression patterns in gonadal cells are largely autonomous. This has provided a unique perspective on CASI in species without traditional chromosomal sex determination systems.{{Cite journal |last1=Jørgensen |first1=Anne |last2=Morthorst |first2=Jane E. |last3=Andersen |first3=Ole |last4=Rasmussen |first4=Lene J. |last5=Bjerregaard |first5=Poul |date=2008-06-30 |title=Expression profiles for six zebrafish genes during gonadal sex differentiation |journal=Reproductive Biology and Endocrinology |volume=6 |issue=1 |pages=25 |doi=10.1186/1477-7827-6-25 |doi-access=free |issn=1477-7827 |pmc=2500022 |pmid=18590525}}{{Cite journal |last1=Small |first1=Clayton M. |last2=Carney |first2=Ginger E. |last3=Mo |first3=Qianxing |last4=Vannucci |first4=Marina |last5=Jones |first5=Adam G. |date=2009-12-03 |title=A microarray analysis of sex- and gonad-biased gene expression in the zebrafish: Evidence for masculinization of the transcriptome |journal=BMC Genomics |volume=10 |issue=1 |pages=579 |doi=10.1186/1471-2164-10-579 |doi-access=free |issn=1471-2164 |pmc=2797025 |pmid=19958554}}{{Cite journal |last1=Pradhan |first1=Ajay |last2=Olsson |first2=Per-Erik |last3=Pradhan |first3=Ajay |last4=Olsson |first4=Per-Erik |date=2016 |title=Regulation of zebrafish gonadal sex differentiation |url=http://www.aimspress.com/article/10.3934/molsci.2016.4.567 |journal=AIMS Molecular Science |language=en |volume=3 |issue=4 |pages=567–584 |doi=10.3934/molsci.2016.4.567 |issn=2372-0301}}

Although CASI is less prominent in mammals due to the dominant role of gonadal hormones, evidence of cell-autonomous sex differences exists. For example, studies in murine models have shown that the presence of XX or XY chromosomes in brain cells can lead to sex-specific differences in neuronal development and function, independent of gonadal hormone influence.{{Cite journal |last1=Wilhelm |first1=Dagmar |last2=Martinson |first2=Fred |last3=Bradford |first3=Stephen |last4=Wilson |first4=Megan J. |last5=Combes |first5=Alexander N. |last6=Beverdam |first6=Annemiek |last7=Bowles |first7=Josephine |last8=Mizusaki |first8=Hirofumi |last9=Koopman |first9=Peter |date=2005-11-01 |title=Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determination |url=https://linkinghub.elsevier.com/retrieve/pii/S001216060500566X |journal=Developmental Biology |volume=287 |issue=1 |pages=111–124 |doi=10.1016/j.ydbio.2005.08.039 |pmid=16185683 |issn=0012-1606}}{{Cite journal |last1=Maekawa |first1=Fumihiko |last2=Sakurai |first2=Miyano |last3=Yamashita |first3=Yuki |last4=Tanaka |first4=Kohichi |last5=Haraguchi |first5=Shogo |last6=Yamamoto |first6=Kazutoshi |last7=Tsutsui |first7=Kazuyoshi |last8=Yoshioka |first8=Hidefumi |last9=Murakami |first9=Shizuko |last10=Tadano |first10=Ryo |last11=Goto |first11=Tatsuhiko |last12=Shiraishi |first12=Jun-ichi |last13=Tomonari |first13=Kohei |last14=Oka |first14=Takao |last15=Ohara |first15=Ken |date=2013-01-22 |title=A genetically female brain is required for a regular reproductive cycle in chicken brain chimeras |url=https://www.nature.com/articles/ncomms2372 |journal=Nature Communications |language=en |volume=4 |issue=1 |pages=1372 |doi=10.1038/ncomms2372 |pmid=23340412 |bibcode=2013NatCo...4.1372M |issn=2041-1723}}{{Cite journal |last1=Kuljis |first1=Dika A. |last2=Loh |first2=Dawn H. |last3=Truong |first3=Danny |last4=Vosko |first4=Andrew M. |last5=Ong |first5=Margaret L. |last6=McClusky |first6=Rebecca |last7=Arnold |first7=Arthur P. |last8=Colwell |first8=Christopher S. |date=2013-04-01 |title=Gonadal- and Sex-Chromosome-Dependent Sex Differences in the Circadian System |journal=Endocrinology |volume=154 |issue=4 |pages=1501–1512 |doi=10.1210/en.2012-1921 |issn=0013-7227 |pmc=3602630 |pmid=23439698}}{{Cite journal |last1=Arnold |first1=Arthur P. |last2=Chen |first2=Xuqi |last3=Link |first3=Jenny C. |last4=Itoh |first4=Yuichiro |last5=Reue |first5=Karen |date=2013 |title=Cell-autonomous sex determination outside of the gonad |journal=Developmental Dynamics |language=en |volume=242 |issue=4 |pages=371–379 |doi=10.1002/dvdy.23936 |issn=1097-0177 |pmc=3672066 |pmid=23361913}}

The nematode Caenorhabditis elegans has provided key insights into CASI in hermaphroditic and male individuals. Sex determination in C. elegans is controlled by the X:A ratio (the number of X chromosomes relative to autosomes), which regulates a cascade of sex-specific gene expression. Each cell independently interprets this ratio, leading to cell-autonomous decisions about sexual differentiation.{{Cite journal |last1=Schedin |first1=Pepper |last2=Hunter |first2=Craig P. |last3=Wood |first3=William B. |date=1991-07-01 |title=Autonomy and nonautonomy of sex determination in triploid intersex mosaics of C. elegans |url=https://journals.biologists.com/dev/article/112/3/863/36847/Autonomy-and-nonautonomy-of-sex-determination-in |journal=Development |volume=112 |issue=3 |pages=863–879 |doi=10.1242/dev.112.3.863 |pmid=1935692 |issn=0950-1991}}{{Cite journal |last=Hodgkin |first=Jonathan |date=1987-03-01 |title=Primary sex determination in the nematode C. elegans |url=https://journals.biologists.com/dev/article/101/Supplement/5/36047/Primary-sex-determination-in-the-nematode-C |journal=Development |volume=101 |issue=Supplement |pages=5–12 |doi=10.1242/dev.101.Supplement.5 |pmid=3503722 |issn=0950-1991}}{{Cite journal |last1=Strome |first1=Susan |last2=Kelly |first2=William G. |last3=Ercan |first3=Sevinc |last4=Lieb |first4=Jason D. |date=2014-03-01 |title=Regulation of the X Chromosomes in Caenorhabditis elegans |url=https://cshperspectives.cshlp.org/content/6/3/a018366 |journal=Cold Spring Harbor Perspectives in Biology |language=en |volume=6 |issue=3 |pages=a018366 |doi=10.1101/cshperspect.a018366 |issn=1943-0264 |pmc=3942922 |pmid=24591522}}{{Cite journal |last=Zarkower |first=David |date=2006 |title=Somatic sex determination |url=http://www.wormbook.org/chapters/www_somaticsexdeterm/somaticsexdeterm.html |journal=WormBook |pages=1–12 |doi=10.1895/wormbook.1.84.1 |pmc=4781091 |pmid=18050479}}

In Lepidoptera, sex determination involves a WZ/ZZ system, similar to birds. Studies have shown that the sex of individual cells is influenced by chromosomal composition, with evidence of CASI playing a significant role in the development of sex-specific traits, such as wing patterns and pheromone production.{{Cite journal |last=MATSUMOTO |first=Shogo |date=2010-02-23 |title=Molecular Mechanisms Underlying Sex Pheromone Production in Moths |url=https://academic.oup.com/bbb/article-abstract/74/2/223/5949497?redirectedFrom=fulltext |journal=Bioscience, Biotechnology, and Biochemistry |volume=74 |issue=2 |pages=223–231 |doi=10.1271/bbb.90756 |pmid=20139627 |issn=0916-8451}}{{Cite journal |last1=Herran |first1=Benjamin |last2=Sugimoto |first2=Takafumi N |last3=Watanabe |first3=Kazuyo |last4=Imanishi |first4=Shigeo |last5=Tsuchida |first5=Tsutomu |last6=Matsuo |first6=Takashi |last7=Ishikawa |first7=Yukio |last8=Kageyama |first8=Daisuke |date=2023-01-01 |title=Cell-based analysis reveals that sex-determining gene signals in Ostrinia are pivotally changed by male-killing Wolbachia |url=https://academic.oup.com/pnasnexus/article/2/1/pgac293/6895556 |journal=PNAS Nexus |volume=2 |issue=1 |pages=pgac293 |doi=10.1093/pnasnexus/pgac293 |issn=2752-6542 |pmc=9837667 |pmid=36712932}}{{Cite journal |last1=Hopkins |first1=Ben R |last2=Kopp |first2=Artyom |date=2021-08-01 |title=Evolution of sexual development and sexual dimorphism in insects |journal=Current Opinion in Genetics & Development |series=Developmental Mechanisms, patterning and evolution |volume=69 |pages=129–139 |doi=10.1016/j.gde.2021.02.011 |issn=0959-437X |pmc=8364864 |pmid=33848958}}{{Cite journal |last1=Yamamoto |first1=Fumiko |last2=Yokoyama |first2=Takeshi |last3=Su |first3=Yan |last4=Suzuki |first4=Masataka G. |date=December 2024 |title=Transcriptomic Evidence for Cell-Autonomous Sex Differentiation of the Gynandromorphic Fat Body in the Silkworm, Bombyx mori |journal=Journal of Developmental Biology |language=en |volume=12 |issue=4 |pages=31 |doi=10.3390/jdb12040031 |doi-access=free |issn=2221-3759 |pmc=11587106 |pmid=39585032}}

The discovery and study of cell autonomous sex identity have far-reaching implications across various fields of biology, medicine, and evolution. By highlighting the intrinsic properties of cells in determining sex-specific traits, CASI has challenged traditional hormone-centric models of sexual differentiation and opened new avenues of research and application.

CASI provides critical insights into the evolution of sex determination systems. The existence of cell-autonomous mechanisms suggests that sex-specific traits can evolve independently of hormonal influences, potentially allowing for greater plasticity in evolutionary pathways. This understanding helps explain the diversity of sex determination strategies observed across taxa, from chromosomal to environmental systems.{{Cite journal |last=Kopp |first=Artyom |date=2012-04-01 |title=Dmrt genes in the development and evolution of sexual dimorphism |journal=Trends in Genetics |language=English |volume=28 |issue=4 |pages=175–184 |doi=10.1016/j.tig.2012.02.002 |issn=0168-9525 |pmc=3350790 |pmid=22425532}}

CASI has redefined our understanding of sexual development by emphasizing the role of intrinsic cellular mechanisms. This has implications for studying developmental disorders related to sexual differentiation, such as androgen insensitivity syndrome and Turner syndrome, as it highlights the interplay between genetic, epigenetic, and cellular factors.{{Cite journal |last1=Luo |first1=Yumei |last2=Zhu |first2=Detu |last3=Du |first3=Rong |last4=Gong |first4=Yu |last5=Xie |first5=Chun |last6=Xu |first6=Xiangye |last7=Fan |first7=Yong |last8=Yu |first8=Bolan |last9=Sun |first9=Xiaofang |last10=Chen |first10=Yaoyong |date=2015-08-25 |title=Uniparental disomy of the entire X chromosome in Turner syndrome patient-specific induced pluripotent stem cells |journal=Cell Discovery |language=en |volume=1 |issue=1 |page=15022 |doi=10.1038/celldisc.2015.22 |issn=2056-5968 |pmc=4860828 |pmid=27462421}}{{Cite journal |last1=Holterhus |first1=Paul-Martin |last2=Deppe |first2=Uta |last3=Werner |first3=Ralf |last4=Richter-Unruh |first4=Annette |last5=Bebermeier |first5=Jan-Hendrik |last6=Wünsch |first6=Lutz |last7=Krege |first7=Susanne |last8=Schweikert |first8=Hans-Udo |last9=Demeter |first9=Janos |last10=Riepe |first10=Felix |last11=Hiort |first11=Olaf |last12=Brooks |first12=James D. |date=2007-10-18 |title=Intrinsic androgen-dependent gene expression patterns revealed by comparison of genital fibroblasts from normal males and individuals with complete and partial androgen insensitivity syndrome |journal=BMC Genomics |volume=8 |issue=1 |pages=376 |doi=10.1186/1471-2164-8-376 |doi-access=free |issn=1471-2164 |pmc=2212662 |pmid=17945006}}{{Cite journal |last1=Holterhus |first1=Paul-Martin |last2=Hiort |first2=Olaf |last3=Demeter |first3=Janos |last4=Brown |first4=Patrick O. |last5=Brooks |first5=James D. |date=2003-05-15 |title=Differential gene-expression patterns in genital fibroblasts of normal males and 46,XY females with androgen insensitivity syndrome: evidence for early programming involving the androgen receptor |journal=Genome Biology |volume=4 |issue=6 |pages=R37 |doi=10.1186/gb-2003-4-6-r37 |doi-access=free |issn=1474-760X |pmc=193616 |pmid=12801411}}{{Cite journal |last=Jääskeläinen |first=Jarmo |date=2012-04-16 |title=Molecular biology of androgen insensitivity |url=https://linkinghub.elsevier.com/retrieve/pii/S0303720711004886 |journal=Molecular and Cellular Endocrinology |series=Androgen Signaling and Receptor |volume=352 |issue=1 |pages=4–12 |doi=10.1016/j.mce.2011.08.006 |pmid=21871529 |issn=0303-7207}}

By exploring CASI across different species, researchers can identify universal and species-specific mechanisms of sexual differentiation. This comparative approach enhances our understanding of how sex-specific traits are regulated in diverse environmental and ecological contexts.{{Cite journal |last1=Rodríguez-Montes |first1=Leticia |last2=Ovchinnikova |first2=Svetlana |last3=Yuan |first3=Xuefei |last4=Studer |first4=Tania |last5=Sarropoulos |first5=Ioannis |last6=Anders |first6=Simon |last7=Kaessmann |first7=Henrik |last8=Cardoso-Moreira |first8=Margarida |date=2023-11-03 |title=Sex-biased gene expression across mammalian organ development and evolution |journal=Science |volume=382 |issue=6670 |pages=eadf1046 |doi=10.1126/science.adf1046 |pmc=7615307 |pmid=37917687|bibcode=2023Sci...382f1046R }}

In mammals, evidence of CASI in brain cells has implications for understanding sex differences in neural development, cognition, and behavior. CASI may contribute to innate sex-specific behaviors and provide new perspectives on the biological basis of neurodevelopmental disorders that exhibit sex-biased prevalence, such as autism spectrum disorder.{{Cite journal |last1=Williams |first1=Olivia O. F. |last2=Coppolino |first2=Madeleine |last3=Perreault |first3=Melissa L. |date=2021-12-09 |title=Sex differences in neuronal systems function and behaviour: beyond a single diagnosis in autism spectrum disorders |journal=Translational Psychiatry |language=en |volume=11 |issue=1 |page=625 |doi=10.1038/s41398-021-01757-1 |issn=2158-3188 |pmc=8660826 |pmid=34887388}}{{Cite journal |last1=Razzak |first1=Rehma |last2=Li |first2=Joy |last3=He |first3=Selena |last4=Sokhadze |first4=Estate |date=November 2023 |title=Investigating Sex-Based Neural Differences in Autism and Their Extended Reality Intervention Implications |journal=Brain Sciences |language=en |volume=13 |issue=11 |pages=1571 |doi=10.3390/brainsci13111571 |doi-access=free |issn=2076-3425 |pmc=10670246 |pmid=38002531}}{{Cite journal |last1=Werling |first1=Donna M. |last2=Parikshak |first2=Neelroop N. |last3=Geschwind |first3=Daniel H. |date=2016-02-19 |title=Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders |journal=Nature Communications |language=en |volume=7 |issue=1 |pages=10717 |doi=10.1038/ncomms10717 |issn=2041-1723 |pmc=4762891 |pmid=26892004|bibcode=2016NatCo...710717W }}

CASI highlights the importance of considering sex as a biological variable in research. Intrinsic differences between male and female cells could influence disease progression, drug responses, and therapeutic outcomes. This understanding emphasizes the need for sex-specific approaches in clinical trials and personalized medicine.{{Cite journal |last1=Ichikawa |first1=Kennosuke |last2=Horiuchi |first2=Hiroyuki |date=March 2023 |title=Fate Decisions of Chicken Primordial Germ Cells (PGCs): Development, Integrity, Sex Determination, and Self-Renewal Mechanisms |journal=Genes |language=en |volume=14 |issue=3 |pages=612 |doi=10.3390/genes14030612 |doi-access=free |issn=2073-4425 |pmc=10048776 |pmid=36980885}}{{Cite journal |last=Capel |first=Blanche |date=2017-08-14 |title=Vertebrate sex determination: evolutionary plasticity of a fundamental switch |url=https://www.nature.com/articles/nrg.2017.60 |journal=Nature Reviews Genetics |language=en |volume=18 |issue=11 |pages=675–689 |doi=10.1038/nrg.2017.60 |pmid=28804140 |issn=1471-0064}}{{Cite journal |last1=Regan |first1=Jennifer C. |last2=Lu |first2=Yu-Xuan |last3=Ureña |first3=Enric |last4=Meilenbrock |first4=Ralf L. |last5=Catterson |first5=James H. |last6=Kißler |first6=Disna |last7=Fröhlich |first7=Jenny |last8=Funk |first8=Emilie |last9=Partridge |first9=Linda |date=2022-12-08 |title=Sexual identity of enterocytes regulates autophagy to determine intestinal health, lifespan and responses to rapamycin |journal=Nature Aging |language=en |volume=2 |issue=12 |pages=1145–1158 |doi=10.1038/s43587-022-00308-7 |issn=2662-8465 |pmc=10154239 |pmid=37118538}}{{Cite journal |last1=Arriola Apelo |first1=Sebastian I |last2=Lin |first2=Amy |last3=Brinkman |first3=Jacqueline A |last4=Meyer |first4=Emma |last5=Morrison |first5=Mark |last6=Tomasiewicz |first6=Jay L |last7=Pumper |first7=Cassidy P |last8=Baar |first8=Emma L |last9=Richardson |first9=Nicole E |last10=Alotaibi |first10=Mohammed |last11=Lamming |first11=Dudley W |date=2020-07-28 |editor-last=Galvan |editor-first=Veronica |editor2-last=Tyler |editor2-first=Jessica K |title=Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging |journal=eLife |volume=9 |pages=e56177 |doi=10.7554/eLife.56177 |doi-access=free |issn=2050-084X |pmc=7386906 |pmid=32720643}}{{Cite journal |last1=Hudry |first1=Bruno |last2=Khadayate |first2=Sanjay |last3=Miguel-Aliaga |first3=Irene |date=2016-12-21 |title=The sexual identity of adult intestinal stem cells controls organ size and plasticity |journal=Nature |language=en |volume=530 |issue=7590 |pages=344–348 |doi=10.1038/nature16953 |issn=1476-4687 |pmc=4800002 |pmid=26887495|bibcode=2016Natur.530..344H }}{{Cite journal |last=Garratt |first=Michael |date=2020-11-03 |title=Why do sexes differ in lifespan extension? Sex-specific pathways of aging and underlying mechanisms for dimorphic responses |url=https://journals.sagepub.com/doi/10.3233/NHA-190067 |journal=Nutrition and Healthy Aging |language=en |volume=5 |issue=4 |pages=247–259 |doi=10.3233/NHA-190067 |issn=2451-9480}}

CASI research can also benefit applied fields like agriculture and wildlife conservation. In poultry farming, for example, understanding CASI may allow for the development of sex-specific growth strategies or improve breeding programs. Similarly, in conservation, insights into CASI could inform efforts to manage populations with skewed sex ratios or develop strategies for assisted reproduction in endangered species.{{Cite journal |last1=Zhang |first1=Xiuan |last2=Li |first2=Jianbo |last3=Chen |first3=Sirui |last4=Yang |first4=Ning |last5=Zheng |first5=Jiangxia |date=2023-05-05 |title=Overview of Avian Sex Reversal |journal=International Journal of Molecular Sciences |language=en |volume=24 |issue=9 |pages=8284 |doi=10.3390/ijms24098284 |doi-access=free |issn=1422-0067 |pmc=10179413 |pmid=37175998}}{{Cite journal |last1=Smith |first1=Craig A. |last2=Sinclair |first2=Andrew H. |date=2004 |title=Sex determination: insights from the chicken |url=https://onlinelibrary.wiley.com/doi/10.1002/bies.10400 |journal=BioEssays |language=en |volume=26 |issue=2 |pages=120–132 |doi=10.1002/bies.10400 |pmid=14745830 |issn=1521-1878}}{{Cite journal |last1=Wildt |first1=David E. |last2=Wemmer |first2=Christen |date=1999-07-01 |title=Sex and wildlife: the role of reproductive science in conservation |url=https://link.springer.com/article/10.1023/A:1008813532763 |journal=Biodiversity & Conservation |language=en |volume=8 |issue=7 |pages=965–976 |doi=10.1023/A:1008813532763 |bibcode=1999BiCon...8..965W |issn=1572-9710}}{{Cite journal |last1=Wilmut |first1=I. |last2=Schnieke |first2=A. E. |last3=McWhir |first3=J. |last4=Kind |first4=A. J. |last5=Campbell |first5=K. H. S. |date=1997-02-27 |title=Viable offspring derived from fetal and adult mammalian cells |url=https://www.nature.com/articles/385810a0 |journal=Nature |language=en |volume=385 |issue=6619 |pages=810–813 |doi=10.1038/385810a0 |pmid=9039911 |bibcode=1997Natur.385..810W |issn=1476-4687}}

While cell autonomous sex identity emphasizes the intrinsic sex-specific properties of individual cells, the interplay between CASI and hormonal influences plays a critical role in shaping an organism's overall sexual phenotype. CASI and hormones are not mutually exclusive but instead represent complementary mechanisms of sexual differentiation.

CASI operates independently of systemic hormonal signals, as demonstrated in studies where individual cells maintain their sexual identity regardless of the hormonal environment. For example, in avian chimeras, male (ZZ) and female (ZW) cells retain their respective gene expression profiles even when transplanted into opposite-sex tissues. This underscores the cell-intrinsic nature of CASI and its role in establishing baseline sex identity at the cellular level.

While CASI establishes the foundational sex identity of a cell, hormones can modulate the expression of CASI-driven traits. For instance, in birds, male and female somatic cells may exhibit intrinsic differences due to CASI, but the extent to which these differences manifest in tissues can be influenced by circulating hormones such as estrogen and testosterone. Hormones act as amplifiers, enhancing or suppressing sex-specific characteristics that are intrinsically determined by CASI.{{Cite journal |last1=Groothuis |first1=Ton G. G. |last2=Hsu |first2=Bin-Yan |last3=Kumar |first3=Neeraj |last4=Tschirren |first4=Barbara |date=2019-02-25 |title=Revisiting mechanisms and functions of prenatal hormone-mediated maternal effects using avian species as a model |journal=Philosophical Transactions of the Royal Society B: Biological Sciences |volume=374 |issue=1770 |pages=20180115 |doi=10.1098/rstb.2018.0115 |pmc=6460091 |pmid=30966885}}{{Cite journal |last1=Lin |first1=Hai-Yan |last2=Song |first2=Gang |last3=Lei |first3=Fumin |last4=Li |first4=Dongming |last5=Qu |first5=Yanhua |date=2021-04-29 |title=Avian corticosteroid-binding globulin: biological function and regulatory mechanisms in physiological stress responses |journal=Frontiers in Zoology |volume=18 |issue=1 |pages=22 |doi=10.1186/s12983-021-00409-w |doi-access=free |issn=1742-9994 |pmc=8086359 |pmid=33926473}}{{Cite journal |last1=Sonnenberg |first1=Benjamin R |last2=Branch |first2=Carrie L |last3=Pitera |first3=Angela M |last4=Benedict |first4=Lauren M |last5=Heinen |first5=Virginia K |last6=Ouyang |first6=Jenny Q |last7=Pravosudov |first7=Vladimir V |date=2024-07-01 |title=Feather growth rate and hormone deposition vary with elevation but not reproductive costs in resident Mountain Chickadees |url=https://academic.oup.com/auk/article-abstract/141/3/ukae011/7625033?redirectedFrom=fulltext |journal=Ornithology |volume=141 |issue=3 |pages=ukae011 |doi=10.1093/ornithology/ukae011 |issn=0004-8038}}

CASI and hormonal influences interact dynamically during development and adulthood:

• Developmental Coordination: In many species, CASI establishes cellular sex identity early in development, which is later reinforced or fine-tuned by hormonal signals. For example, in mammals, the SRY gene on the Y chromosome initiates testis development, but subsequent male sexual differentiation heavily relies on androgens.{{Cite journal |last=Hiort |first=Olaf |date=2013-06-24 |title=The differential role of androgens in early human sex development |journal=BMC Medicine |volume=11 |issue=1 |pages=152 |doi=10.1186/1741-7015-11-152 |doi-access=free |issn=1741-7015 |pmc=3706224 |pmid=23800242}}
• Sexual Dimorphism: The combined effects of CASI and hormones contribute to the development of sexually dimorphic traits. In some cases, CASI may dictate cellular predispositions, while hormones ensure the coordinated expression of these traits across tissues and organs.{{Cite journal |last1=Yuan |first1=Xin |last2=Lu |first2=Michael L. |last3=Li |first3=Tong |last4=Balk |first4=Steven P. |date=2001-12-07 |title=SRY Interacts with and Negatively Regulates Androgen Receptor Transcriptional Activity * |journal=Journal of Biological Chemistry |language=English |volume=276 |issue=49 |pages=46647–46654 |doi=10.1074/jbc.M108404200 |doi-access=free |issn=0021-9258 |pmid=11585838}}

Instances where CASI and hormonal influences diverge provide unique insights into their interplay. For example:

• Chimeric Studies: In mixed-sex chimeras, cells maintain CASI-determined sexual identity even when exposed to conflicting hormonal environments.{{Cite journal |last1=Eckardt |first1=Sigrid |last2=McLaughlin |first2=K. John |last3=Willenbring |first3=Holger |title=Mouse chimeras as a system to investigate development, cell and tissue function, disease mechanisms and organ regeneration |journal=Cell Cycle |date=2011-07-01 |volume=10 |issue=13 |pages=2091–2099 |doi=10.4161/cc.10.13.16360 |issn=1538-4101 |pmc=3230469 |pmid=21606677}}{{Cite journal |last1=Gardner |first1=R. L. |last2=Johnson |first2=M. H. |date=1973-11-21 |title=Investigation of Early Mammalian Development using Interspecific Chimaeras between Rat and Mouse |url=https://www.nature.com/articles/newbio246086a0 |journal=Nature New Biology |language=en |volume=246 |issue=151 |pages=86–89 |doi=10.1038/newbio246086a0 |pmid=4586447 |issn=2058-1092}}
• Hormone Insensitivity Syndromes: Disorders like androgen insensitivity syndrome (AIS) reveal the limitations of hormonal influence when CASI-driven traits dominate cellular responses. In AIS, individuals with XY chromosomes (CASI-determined male identity) develop phenotypically female characteristics due to a lack of response to androgens.{{Cite journal |last1=Batista |first1=Rafael Loch |last2=Costa |first2=Elaine M. Frade |last3=Rodrigues |first3=Andresa de Santi |last4=Gomes |first4=Nathalia Lisboa |last5=Faria Jr. |first5=José Antonio |last6=Nishi |first6=Mirian Y. |last7=Arnhold |first7=Ivo Jorge Prado |last8=Domenice |first8=Sorahia |last9=Mendonca |first9=Berenice Bilharinho de |date=2018-03-23 |title=Androgen insensitivity syndrome: a review |journal=Archives of Endocrinology and Metabolism |language=en |volume=62 |issue=2 |pages=227–235 |doi=10.20945/2359-3997000000031 |issn=2359-3997 |pmc=10118986 |pmid=29768628}}

Understanding the interaction between CASI and hormonal influences has profound implications:

• Endocrinology: Investigating how CASI interacts with hormone-driven processes can provide deeper insights into endocrine disorders.{{Cite journal |last1=Lauretta |first1=R. |last2=Sansone |first2=M. |last3=Sansone |first3=A. |last4=Romanelli |first4=F. |last5=Appetecchia |first5=M. |date=2018 |title=Gender in Endocrine Diseases: Role of Sex Gonadal Hormones |journal=International Journal of Endocrinology |language=en |volume=2018 |issue=1 |pages=4847376 |doi=10.1155/2018/4847376 |doi-access=free |issn=1687-8345 |pmc=6215564 |pmid=30420884}}{{Cite journal |last1=Blenck |first1=Christa L. |last2=Harvey |first2=Pamela A. |last3=Reckelhoff |first3=Jane F. |last4=Leinwand |first4=Leslie A. |date=2016-04-15 |title=The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease |journal=Circulation Research |volume=118 |issue=8 |pages=1294–1312 |doi=10.1161/CIRCRESAHA.116.307509 |pmc=4834858 |pmid=27081111}}
• Regenerative Medicine: Incorporating both CASI and hormonal influences in tissue engineering could improve outcomes for sex-specific therapies.{{Cite journal |last1=Böhm |first1=Christian |last2=Benz |first2=Verena |last3=Clemenz |first3=Markus |last4=Sprang |first4=Christiane |last5=Höft |first5=Beata |last6=Kintscher |first6=Ulrich |last7=Foryst-Ludwig |first7=Anna |date=2013-07-15 |title=Sexual dimorphism in obesity-mediated left ventricular hypertrophy |url=https://journals.physiology.org/doi/full/10.1152/ajpheart.00593.2012 |journal=American Journal of Physiology-Heart and Circulatory Physiology |volume=305 |issue=2 |pages=H211–H218 |doi=10.1152/ajpheart.00593.2012 |pmid=23666673 |issn=0363-6135}}
• Sex Differences in Disease: CASI may explain intrinsic cellular differences between males and females that persist even when hormonal effects are absent or minimized.{{Cite journal |last1=Lauretta |first1=Rosa |last2=Sansone |first2=Massimiliano |last3=Romanelli |first3=Francesco |last4=Appetecchia |first4=Marialuisa |date=2017-07-01 |title=Gender in endocrinological diseases: biological and clinical differences |url=https://www.gendermedjournal.it/archivio/2882/articoli/29060/ |journal=Journal of Sex- and Gender-Specific Medicine |language=it |volume=3 |issue=3 |pages=109–116 |doi=10.1723/2882.29060}}{{Cite journal |last1=Shi |first1=Wei |last2=Sheng |first2=Xinlei |last3=Dorr |first3=Kerry M. |last4=Hutton |first4=Josiah E. |last5=Emerson |first5=James I. |last6=Davies |first6=Haley A. |last7=Andrade |first7=Tia D. |last8=Wasson |first8=Lauren K. |last9=Greco |first9=Todd M. |last10=Hashimoto |first10=Yutaka |last11=Federspiel |first11=Joel D. |last12=Robbe |first12=Zachary L. |last13=Chen |first13=Xuqi |last14=Arnold |first14=Arthur P. |last15=Cristea |first15=Ileana M. |date=2021-11-08 |title=Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation |journal=Developmental Cell |language=English |volume=56 |issue=21 |pages=3019–3034.e7 |doi=10.1016/j.devcel.2021.09.022 |issn=1534-5807 |pmc=9290207 |pmid=34655525}}{{Cite journal |last1=Arnold |first1=Arthur P. |last2=Cassis |first2=Lisa A. |last3=Eghbali |first3=Mansoureh |last4=Reue |first4=Karen |last5=Sandberg |first5=Kathryn |date=2017-05-01 |title=Sex Hormones and Sex Chromosomes Cause Sex Differences in the Development of Cardiovascular Diseases |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |language=en |volume=37 |issue=5 |pages=746–756 |doi=10.1161/ATVBAHA.116.307301 |issn=1079-5642 |pmc=5437981 |pmid=28279969}}{{Cite journal |last1=Christou |first1=Evangelos A A |last2=Banos |first2=Aggelos |last3=Kosmara |first3=Despoina |last4=Bertsias |first4=George K |last5=Boumpas |first5=Dimitrios T |date=2019-01-01 |title=Sexual dimorphism in SLE: above and beyond sex hormones |journal=Lupus |language=en |volume=28 |issue=1 |pages=3–10 |doi=10.1177/0961203318815768 |issn=0961-2033 |pmc=6304686 |pmid=30501463}}

The study of cell autonomous sex identity offers profound insights into the evolution of sex determination and differentiation across species. CASI reveals an evolutionary framework that integrates cell-intrinsic mechanisms with broader hormonal systems, providing adaptability and resilience in diverse ecological and environmental contexts.

CASI represents an ancient and conserved mechanism for sex determination that predates the evolution of complex hormonal systems. The ability of individual cells to autonomously interpret genetic cues and establish their sexual identity is evident across a wide range of taxa, from simple invertebrates like Drosophila to more complex vertebrates such as birds. This suggests that CASI is a fundamental evolutionary strategy, ensuring sex-specific cellular function at the earliest stages of multicellular organismal development.{{Cite journal |last1=Márquez-Zacarías |first1=Pedro |last2=Pineau |first2=Rozenn M. |last3=Gomez |first3=Marcella |last4=Veliz-Cuba |first4=Alan |last5=Murrugarra |first5=David |last6=Ratcliff |first6=William C. |last7=Niklas |first7=Karl J. |date=2021-01-01 |title=Evolution of Cellular Differentiation: From Hypotheses to Models |url=https://linkinghub.elsevier.com/retrieve/pii/S0169534720302081 |journal=Trends in Ecology & Evolution |language=English |volume=36 |issue=1 |pages=49–60 |doi=10.1016/j.tree.2020.07.013 |issn=0169-5347 |pmid=32829916|bibcode=2021TEcoE..36...49M }}{{Cite journal |last=Chatterjee |first=Rabindra Nath |date=2024-08-01 |title=Sex determining systems of Drosophila control somatic sexual differentiation by cytoplasmic determinants and inductive signals: an insight from pattern development of aberrant sexual genotypes |url=https://link.springer.com/article/10.1007/s13237-023-00429-3 |journal=The Nucleus |language=en |volume=67 |issue=2 |pages=277–289 |doi=10.1007/s13237-023-00429-3 |issn=0976-7975}}{{Cite journal |last=Bachtrog |first=Doris |date=2014-08-04 |title=Y-chromosome evolution: emerging insights into processes of Y-chromosome degeneration |journal=Nature Reviews. Genetics |volume=14 |issue=2 |pages=113–124 |doi=10.1038/nrg3366 |issn=1471-0064 |pmc=4120474 |pmid=23329112}}

As organisms evolved, systemic hormonal systems likely arose to coordinate sex-specific traits across tissues and organs, supplementing the intrinsic mechanisms provided by CASI. This dual system allowed for more complex sexual dimorphisms and greater adaptability to environmental pressures, such as mate competition and reproductive success. The divergence of hormonal regulation in mammals (testosterone and estrogen dominance) and birds (estradiol-driven mechanisms) reflects evolutionary fine-tuning built upon the foundation of CASI.{{Cite journal |last=Adkins-Regan |first=Elizabeth |date=2007-11-28 |title=Do hormonal control systems produce evolutionary inertia? |journal=Philosophical Transactions of the Royal Society B: Biological Sciences |volume=363 |issue=1497 |pages=1599–1609 |doi=10.1098/rstb.2007.0005 |pmc=2606723 |pmid=18048293}}{{Cite journal |last1=De Jesus |first1=Anne Nicole |last2=Henry |first2=Belinda A. |date=2023 |title=The role of oestrogen in determining sexual dimorphism in energy balance |journal=The Journal of Physiology |language=en |volume=601 |issue=3 |pages=435–449 |doi=10.1113/JP279501 |issn=1469-7793 |pmc=10092637 |pmid=36117117}}{{Cite journal |last1=Peterson |first1=Mark P. |last2=Rosvall |first2=Kimberly A. |last3=Choi |first3=Jeong-Hyeon |last4=Ziegenfus |first4=Charles |last5=Tang |first5=Haixu |last6=Colbourne |first6=John K. |last7=Ketterson |first7=Ellen D. |date=2013-04-16 |title=Testosterone Affects Neural Gene Expression Differently in Male and Female Juncos: A Role for Hormones in Mediating Sexual Dimorphism and Conflict |journal=PLOS ONE |language=en |volume=8 |issue=4 |pages=e61784 |doi=10.1371/journal.pone.0061784 |doi-access=free |issn=1932-6203 |pmc=3627916 |pmid=23613935|bibcode=2013PLoSO...861784P }}

CASI has implications for understanding the evolution of sex chromosomes. The ability of cells to interpret sex chromosome composition autonomously may have driven the specialization of sex chromosomes, such as the differentiation of X and Y in mammals and Z and W in birds. In species where chromosomal sex determination is absent or secondary, as in zebrafish or certain reptiles, CASI may provide insights into how sex identity is maintained in the absence of clear chromosomal cues.{{Cite web |title=The evolution of the sex chromosomes Step by step - UChicago Medicine |url=https://www.uchicagomedicine.org/forefront/news/the-evolution-of-the-sex-chromosomes-step-by-step |access-date=2025-01-18 |website=www.uchicagomedicine.org |language=en}}{{Cite journal |date=2004-12-21 |title=Evolution of Sex Chromosomes: The Case of the White Campion |journal=PLOS Biology |language=en |volume=3 |issue=1 |pages=e28 |doi=10.1371/journal.pbio.0030028 |doi-access=free |issn=1545-7885 |pmc=536008}}{{Cite journal |last1=Valdivieso |first1=Alejandro |last2=Wilson |first2=Catherine A. |last3=Amores |first3=Angel |last4=da Silva Rodrigues |first4=Maira |last5=Nóbrega |first5=Rafael Henrique |last6=Ribas |first6=Laia |last7=Postlethwait |first7=John H. |last8=Piferrer |first8=Francesc |date=2022-10-01 |title=Environmentally-induced sex reversal in fish with chromosomal vs. polygenic sex determination |journal=Environmental Research |volume=213 |pages=113549 |doi=10.1016/j.envres.2022.113549 |issn=0013-9351 |pmc=9620983 |pmid=35618011|bibcode=2022ER....21313549V }}

The cell-autonomous nature of CASI offers several evolutionary advantages:

• Resilience to Environmental Fluctuations: CASI ensures intrinsic sex determination at the cellular level, which may be less susceptible to environmental perturbations than hormonal systems.{{Cite journal |last1=Natri |first1=Heini M. |last2=Merilä |first2=Juha |last3=Shikano |first3=Takahito |date=2019-01-11 |title=The evolution of sex determination associated with a chromosomal inversion |journal=Nature Communications |language=en |volume=10 |issue=1 |pages=145 |doi=10.1038/s41467-018-08014-y |issn=2041-1723 |pmc=6329827 |pmid=30635564|bibcode=2019NatCo..10..145N }}{{Cite journal |last1=Schenkel |first1=Martijn A |last2=Billeter |first2=Jean-Christophe |last3=Beukeboom |first3=Leo W |last4=Pen |first4=Ido |date=2023-06-01 |title=Divergent evolution of genetic sex determination mechanisms along environmental gradients |url=https://academic.oup.com/evlett/article/7/3/132/7099505 |journal=Evolution Letters |volume=7 |issue=3 |pages=132–147 |doi=10.1093/evlett/qrad011 |issn=2056-3744 |pmc=10210438 |pmid=37251583}}
• Tissue-Specific Adaptation: CASI allows for the independent evolution of sex-specific traits in different tissues, enabling specialized functions that enhance reproductive success and survival.
• Flexibility in Evolutionary Pathways: CASI provides a substrate for the evolution of diverse sex determination systems, allowing species to adapt sex determination strategies to ecological niches or environmental constraints.{{Cite journal |last1=Bachtrog |first1=Doris |last2=Mank |first2=Judith E. |last3=Peichel |first3=Catherine L. |last4=Kirkpatrick |first4=Mark |last5=Otto |first5=Sarah P. |last6=Ashman |first6=Tia-Lynn |last7=Hahn |first7=Matthew W. |last8=Kitano |first8=Jun |last9=Mayrose |first9=Itay |last10=Ming |first10=Ray |last11=Perrin |first11=Nicolas |last12=Ross |first12=Laura |last13=Valenzuela |first13=Nicole |last14=Vamosi |first14=Jana C. |last15=Consortium |first15=The Tree of Sex |date=2014-07-01 |title=Sex Determination: Why So Many Ways of Doing It? |journal=PLOS Biology |language=en |volume=12 |issue=7 |pages=e1001899 |doi=10.1371/journal.pbio.1001899 |doi-access=free |issn=1545-7885 |pmc=4077654 |pmid=24983465}}

Studies of CASI across taxa reveal evolutionary trade-offs between cell-autonomous mechanisms and hormonal regulation. For example:

• Birds and Mammals: The prominence of CASI in birds contrasts with the hormone-dominated systems of mammals, highlighting different evolutionary pressures shaping sex determination.{{Cite journal |last1=Wang |first1=Zongji |last2=Zhang |first2=Jilin |last3=Yang |first3=Wei |last4=An |first4=Na |last5=Zhang |first5=Pei |last6=Zhang |first6=Guojie |last7=Zhou |first7=Qi |date=2014-12-12 |title=Temporal genomic evolution of bird sex chromosomes |journal=BMC Evolutionary Biology |volume=14 |issue=1 |pages=250 |doi=10.1186/s12862-014-0250-8 |doi-access=free |issn=1471-2148 |pmc=4272511 |pmid=25527260|bibcode=2014BMCEE..14..250W }}{{Cite journal |last=Ellegren |first=Hans |date=2000-05-01 |title=Evolution of the avian sex chromosomes and their role in sex determination |url=https://linkinghub.elsevier.com/retrieve/pii/S0169534700018218 |journal=Trends in Ecology & Evolution |language=English |volume=15 |issue=5 |pages=188–192 |doi=10.1016/S0169-5347(00)01821-8 |issn=0169-5347 |pmid=10782132}}{{Citation |last1=Sinclair |first1=Andrew |title=A Comparative Analysis of Vertebrate Sex Determination |date=2002 |work=The Genetics and Biology of Sex Determination |pages=102–114 |url=https://onlinelibrary.wiley.com/doi/10.1002/0470868732.ch10 |access-date=2025-01-18 |publisher=John Wiley & Sons, Ltd |language=en |doi=10.1002/0470868732.ch10 |isbn=978-0-470-86873-7 |last2=Smith |first2=Craig |last3=Western |first3=Patrick |last4=McClive |first4=Peter|volume=244 |pmid=11990786 }}
• Invertebrates and Vertebrates: The conservation of CASI in invertebrates, such as Drosophila, and its adaptation in vertebrates illustrates how intrinsic sex determination mechanisms have been modified across evolutionary time scales.{{Cite journal |last1=Uller |first1=Tobias |last2=Pen |first2=Ido |last3=Wapstra |first3=Erik |last4=Beukeboom |first4=Leo W. |last5=Komdeur |first5=Jan |date=2007-06-01 |title=The evolution of sex ratios and sex-determining systems |url=https://linkinghub.elsevier.com/retrieve/pii/S0169534707000997 |journal=Trends in Ecology & Evolution |language=English |volume=22 |issue=6 |pages=292–297 |doi=10.1016/j.tree.2007.03.008 |issn=0169-5347 |pmid=17418448|bibcode=2007TEcoE..22..292U }}{{Cite journal |last=Doorn |first=G. Sander van |date=2014-08-01 |title=Patterns and Mechanisms of Evolutionary Transitions between Genetic Sex-Determining Systems |url=https://cshperspectives.cshlp.org/content/6/8/a017681 |journal=Cold Spring Harbor Perspectives in Biology |language=en |volume=6 |issue=8 |pages=a017681 |doi=10.1101/cshperspect.a017681 |issn=1943-0264 |pmc=4107992 |pmid=24993578}}{{Cite journal |last1=De Loof |first1=Arnold |last2=Huybrechts |first2=Jurgen |last3=Geens |first3=Marisa |last4=Vandersmissen |first4=Tim |last5=Boerjan |first5=Bart |last6=Schoofs |first6=Liliane |date=2010-08-01 |title=Sexual differentiation in adult insects: Male-specific cuticular yellowing in Schistocerca gregaria as a model for reevaluating some current (neuro)endocrine concepts |url=https://linkinghub.elsevier.com/retrieve/pii/S0022191010000703 |journal=Journal of Insect Physiology |series=Locust Research in the Age of Model Organisms In honor of M.P. Pener's 80th Birthday |volume=56 |issue=8 |pages=919–925 |doi=10.1016/j.jinsphys.2010.02.021 |pmid=20223244 |bibcode=2010JInsP..56..919D |issn=0022-1910}}

CASI underscores the importance of considering multiple levels of biological organization in evolution. While hormones allow for organism-wide coordination, CASI demonstrates cellular-level autonomy in driving evolutionary change. This duality provides a robust framework for the emergence and maintenance of sex-specific traits across a wide variety of life forms.

The study of cell autonomous sex identity in humans is an emerging field that offers new insights into sex differentiation, disorders of sexual development (DSDs), and broader aspects of human biology. While hormonal signals are well-known to play a key role in sexual differentiation, CASI presents a crucial layer of regulation that operates at the cellular level, influencing how human cells "decide" their sex identity independent of external hormonal cues. This section explores the implications of CASI for human biology, from sexual development to disease and beyond.

CASI plays a foundational role in early sexual differentiation in humans, particularly during embryonic development. In XY embryos, the SRY gene on the Y chromosome activates a cascade of signals that trigger testis development, while in XX embryos, the absence of SRY leads to ovarian development. While hormones such as testosterone and estrogen play major roles in furthering sexual development and secondary sexual characteristics, CASI ensures that each cell reflects its genetic sex, whether male (XY) or female (XX), from the very beginning.{{Cite journal |last=Fechner |first=Patricia Y |date=1996 |title=The role of SRY in mammalian sex determination |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1442-200X.1996.tb03512.x |journal=Pediatrics International |language=en |volume=38 |issue=4 |pages=380–389 |doi=10.1111/j.1442-200X.1996.tb03512.x |pmid=8840551 |issn=1442-200X}}{{Cite journal |last=Koopman |first=P. |date=1999-06-01 |title=Sry and Sox9: mammalian testis-determining genes |journal=Cellular and Molecular Life Sciences |language=en |volume=55 |issue=6 |pages=839–856 |doi=10.1007/PL00013200 |issn=1420-9071 |pmc=11146764 |pmid=10412367}}{{Cite journal |last1=Wijchers |first1=Patrick J. |last2=Yandim |first2=Cihangir |last3=Panousopoulou |first3=Eleni |last4=Ahmad |first4=Mushfika |last5=Harker |first5=Nicky |last6=Saveliev |first6=Alexander |last7=Burgoyne |first7=Paul S. |last8=Festenstein |first8=Richard |date=2010-09-14 |title=Sexual Dimorphism in Mammalian Autosomal Gene Regulation Is Determined Not Only by Sry but by Sex Chromosome Complement As Well |url=https://linkinghub.elsevier.com/retrieve/pii/S1534580710003801 |journal=Developmental Cell |language=English |volume=19 |issue=3 |pages=477–484 |doi=10.1016/j.devcel.2010.08.005 |issn=1534-5807 |pmid=20833369}}

Research has shown that cells, particularly in the gonads, brain, and other tissues, retain their cellular sex identity even in conditions where hormonal signals might be disrupted or absent. This independent cellular identity suggests that CASI might be at work throughout human development, regulating key processes such as the differentiation of gonads and the central nervous system.{{Cite journal |last=Hines |first=Melissa |date=2010-10-01 |title=Sex-related variation in human behavior and the brain |journal=Trends in Cognitive Sciences |language=English |volume=14 |issue=10 |pages=448–456 |doi=10.1016/j.tics.2010.07.005 |issn=1364-6613 |pmc=2951011 |pmid=20724210}}{{Cite journal |last1=Ocañas |first1=Sarah R. |last2=Ansere |first2=Victor A. |last3=Kellogg |first3=Collyn M. |last4=Isola |first4=Jose V. V. |last5=Chucair-Elliott |first5=Ana J. |last6=Freeman |first6=Willard M. |date=2023-04-01 |title=Chromosomal and gonadal factors regulate microglial sex effects in the aging brain |journal=Brain Research Bulletin |volume=195 |pages=157–171 |doi=10.1016/j.brainresbull.2023.02.008 |issn=0361-9230 |pmc=10810555 |pmid=36804773}}{{Cite journal |last1=Snell |first1=Daniel M. |last2=Turner |first2=James M. A. |date=2018-11-19 |title=Sex Chromosome Effects on Male–Female Differences in Mammals |journal=Current Biology |language=English |volume=28 |issue=22 |pages=R1313–R1324 |doi=10.1016/j.cub.2018.09.018 |issn=0960-9822 |pmc=6264392 |pmid=30458153|bibcode=2018CBio...28R1313S }}{{Cite journal |last1=Malone |first1=P. S. |last2=Hall-Craggs |first2=M. A. |last3=Mouriquand |first3=P. D. E. |last4=Caldamone |first4=A. A. |date=2012-12-01 |title=The anatomical assessment of disorders of sex development (DSD) |url=https://linkinghub.elsevier.com/retrieve/pii/S1477513112002185 |journal=Journal of Pediatric Urology |language=English |volume=8 |issue=6 |pages=585–591 |doi=10.1016/j.jpurol.2012.08.009 |issn=1477-5131 |pmid=22995869}}

Understanding CASI is crucial for interpreting certain disorders of sexual development (DSDs), in which an individual's chromosomal sex and phenotypic sex do not align as expected. These conditions can be classified into several categories, including conditions where individuals with XY chromosomes develop female characteristics (e.g., androgen insensitivity syndrome) or individuals with XX chromosomes develop male characteristics (e.g., congenital adrenal hyperplasia).{{Cite journal |last1=Martinez de LaPiscina |first1=Idoia |last2=Flück |first2=Christa E. |date=2021-12-01 |title=Genetics of human sexual development and related disorders |url=https://journals.lww.com/co-pediatrics/abstract/2021/12000/genetics_of_human_sexual_development_and_related.4.aspx |journal=Current Opinion in Pediatrics |language=en-US |volume=33 |issue=6 |pages=556–563 |doi=10.1097/MOP.0000000000001066 |pmid=34654048 |issn=1040-8703}}{{Cite journal |last1=Eggers |first1=Stefanie |last2=Sadedin |first2=Simon |last3=van den Bergen |first3=Jocelyn A. |last4=Robevska |first4=Gorjana |last5=Ohnesorg |first5=Thomas |last6=Hewitt |first6=Jacqueline |last7=Lambeth |first7=Luke |last8=Bouty |first8=Aurore |last9=Knarston |first9=Ingrid M. |last10=Tan |first10=Tiong Yang |last11=Cameron |first11=Fergus |last12=Werther |first12=George |last13=Hutson |first13=John |last14=O’Connell |first14=Michele |last15=Grover |first15=Sonia R. |date=2016-11-29 |title=Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort |journal=Genome Biology |volume=17 |issue=1 |pages=243 |doi=10.1186/s13059-016-1105-y |doi-access=free |issn=1474-760X |pmc=5126855 |pmid=27899157}}

In cases such as androgen insensitivity syndrome (AIS), cells that would typically be influenced by testosterone fail to respond to the hormone, resulting in the development of female external genitalia despite the presence of a Y chromosome. However, the intrinsic cellular identity of the individual’s cells, as determined by their chromosomal sex (XX or XY), remains intact at the cellular level, which aligns with CASI. This suggests that CASI can influence the phenotypic sex independently of hormonal signaling.{{Cite journal |last1=Guo |first1=Min |last2=Huang |first2=Jin-Cheng |last3=Li |first3=Cui-Fen |last4=Liu |first4=Yan-Yan |date=2023-02-01 |title=Complete androgen insensitivity syndrome: a case report and literature review |journal=Journal of International Medical Research |language=en |volume=51 |issue=2 |pages=03000605231154413 |doi=10.1177/03000605231154413 |issn=0300-0605 |pmc=9983103 |pmid=36851849}}{{Cite journal |last=De Vries |first=Geert J. |date=2004-03-01 |title=Minireview: Sex Differences in Adult and Developing Brains: Compensation, Compensation, Compensation |url=https://academic.oup.com/endo/article-abstract/145/3/1063/2877962?redirectedFrom=fulltext |journal=Endocrinology |volume=145 |issue=3 |pages=1063–1068 |pmid=14670982 |issn=0013-7227}}

CASI’s role in human brain development is another important aspect of its contribution to human biology. There is increasing evidence that CASI may contribute to sex differences in brain structures and functions, potentially influencing cognition, behavior, and neurological conditions. Research in humans and animal models has suggested that sexual differentiation in the brain begins early in development, and that certain brain cells might maintain their intrinsic sex identity, even in the absence of external hormonal signaling.

For example, while hormones such as estrogen and testosterone are known to influence brain sexual differentiation in typical sexual development, there may also be cellular mechanisms driven by CASI that set the foundation for sexually dimorphic traits in the brain, including differences in regions responsible for motor control, spatial ability, and emotional regulation. These findings could be important for understanding sex-based differences in neurodevelopmental disorders, such as autism spectrum disorder (ASD), which shows a higher prevalence in males.

The implications of CASI extend to human health, especially in relation to sex-specific diseases. While hormonal influences have long been studied in diseases such as cancer (e.g., prostate cancer, ovarian cancer), CASI suggests that the cellular sex identity may also contribute to disease susceptibility and progression.{{Cite journal |last1=van Nas |first1=Atila |last2=GuhaThakurta |first2=Debraj |last3=Wang |first3=Susanna S. |last4=Yehya |first4=Nadir |last5=Horvath |first5=Steve |last6=Zhang |first6=Bin |last7=Ingram-Drake |first7=Leslie |last8=Chaudhuri |first8=Gautam |last9=Schadt |first9=Eric E. |last10=Drake |first10=Thomas A. |last11=Arnold |first11=Arthur P. |last12=Lusis |first12=Aldons J. |date=2009-03-01 |title=Elucidating the Role of Gonadal Hormones in Sexually Dimorphic Gene Coexpression Networks |journal=Endocrinology |volume=150 |issue=3 |pages=1235–1249 |doi=10.1210/en.2008-0563 |issn=0013-7227 |pmc=2654741 |pmid=18974276}}{{Cite journal |last1=Zore |first1=Temeka |last2=Palafox |first2=Maria |last3=Reue |first3=Karen |date=2018-09-01 |title=Sex differences in obesity, lipid metabolism, and inflammation—A role for the sex chromosomes? |journal=Molecular Metabolism |series=Sex and Gender Differences in Metabolism (2018) |volume=15 |pages=35–44 |doi=10.1016/j.molmet.2018.04.003 |issn=2212-8778 |pmc=6066740 |pmid=29706320}}{{Cite journal |last1=Rubin |first1=Joshua B. |last2=Lagas |first2=Joseph S. |last3=Broestl |first3=Lauren |last4=Sponagel |first4=Jasmin |last5=Rockwell |first5=Nathan |last6=Rhee |first6=Gina |last7=Rosen |first7=Sarah F. |last8=Chen |first8=Si |last9=Klein |first9=Robyn S. |last10=Imoukhuede |first10=Princess |last11=Luo |first11=Jingqin |date=2020-04-15 |title=Sex differences in cancer mechanisms |journal=Biology of Sex Differences |volume=11 |issue=1 |pages=17 |doi=10.1186/s13293-020-00291-x |doi-access=free |issn=2042-6410 |pmc=7161126 |pmid=32295632}}

For example, in certain types of cancers, such as breast cancer or ovarian cancer, the intrinsic sex identity of cells could affect their behavior, such as their response to treatment, their rate of growth, and their metastatic potential. Investigating CASI could help elucidate why some diseases manifest differently in males and females and why certain diseases are sex biased.{{Cite journal |last1=Kaminsky |first1=Zachary |last2=Wang |first2=Sun-Chong |last3=Petronis |first3=Arturas |date=2006-01-01 |title=Complex disease, gender and epigenetics |url=https://www.tandfonline.com/doi/full/10.1080/07853890600989211 |journal=Annals of Medicine |volume=38 |issue=8 |pages=530–544 |doi=10.1080/07853890600989211 |pmid=17438668 |issn=0785-3890}}{{Cite journal |last1=Ober |first1=Carole |last2=Loisel |first2=Dagan A. |last3=Gilad |first3=Yoav |date=2008-12-01 |title=Sex-specific genetic architecture of human disease |journal=Nature Reviews Genetics |language=en |volume=9 |issue=12 |pages=911–922 |doi=10.1038/nrg2415 |issn=1471-0064 |pmc=2694620 |pmid=19002143}}

• Sex determination
• Sexual dimorphism
• Gonadal development
• SRY gene

Category:Evolution

Category:Sexual dimorphism

Category:Genetics

Category:Cell biology