sex-lethal

In D. melanogaster, Sxl exerts its effects primarily through post-transcriptional regulation, specifically alternative splicing and translational repression. It regulates at least three key target genes: *Sxl* itself (autoregulation), *transformer (tra)* (sex determination), and *male-specific lethal-2 (msl-2)* (dosage compensation).

Sxl regulates its own expression through a positive feedback loop in females. This involves alternative splicing of the *Sxl* pre-mRNA. In males, the *Sxl* transcript includes a "male-specific exon" (exon 3) that contains an early stop codon, resulting in a truncated, non-functional protein. In females, Sxl protein binds to its own pre-mRNA at multiple sites, both upstream and downstream of the male-specific exon. This binding primarily influences the selection of the 5' splice site of the male exon, promoting the skipping of the male-specific exon and the production of a full-length, functional Sxl protein.{{cite journal | vauthors = Horabin JI, Emmons AT, VanVickle-Chavez SJ, Chen T | title = Distinct regulatory steps in the Drosophila sex determination pathway use Sex-lethal to exert analog control | journal = Genetics | volume = 199 | issue = 2 | pages = 509–23 | date = February 2015 | pmid = 25635454 | doi = 10.1016/j.cell.2015.01.013 | pmc = 4349088 }}{{cite journal | vauthors = Klein ME, Moursi A, Mer G, Rio DC | title = Mechanism of regulated alternative 5' splice site selection by Drosophila Sex-lethal | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 27 | pages = 15721–15731 | date = July 2020 | pmid = 32539959 | doi = 10.1016/j.fm.2020.103532 | doi-access = free | pmc = 7345674 | bibcode = 2020PNAS..11715721K }} The protein PPS interacts with Sxl and helps mediate this effect.

In fruit flies, Sxl protein participates in alternative splicing of the transformer gene, ultimately deciding the sex of the fly.{{cite journal | vauthors = Bell LR, Maine EM, Schedl P, Cline TW | title = Sex-lethal, a Drosophila sex determination switch gene, exhibits sex-specific RNA splicing and sequence similarity to RNA binding proteins | journal = Cell | volume = 55 | issue = 6 | pages = 1037–46 | date = December 1988 | pmid = 3144435 | doi = 10.1016/0092-8674(88)90248-6 | s2cid = 22691059 }} Sxl induces female-specific alternative splicing of the transformer (tra) pre-mRNA by binding to uridine-rich polypyrimidine tracts near the non-sex-specific 3' splice site. This binding prevents the general splicing factor U2AF from binding, thus promoting the use of a female-specific upstream 3' splice site.

Sxl regulates *male-specific lethal-2 (msl-2)*, a key component of the dosage compensation complex, through a combination of alternative splicing and translational repression.{{cite journal | vauthors = Kelley RL, Wang J, Bell L, Kuroda MI | title = Sex-lethal controls dosage compensation in Drosophila by a non-splicing mechanism | journal = Nature | volume = 377 | issue = 6548 | pages = 428–31 | date = October 1995 | pmid = 7566118 | doi = 10.1038/377428a0 | bibcode = 1995Natur.377..428K | s2cid = 4292579}}{{cite journal | vauthors = Merz J, Ghosh S, Bellini D, Pipalia T, Shcherbakova I, Huang SC, Gehring NH, Hiller M, Kaygun H, Zavolan M, Ghosh G | title = Molecular mechanism and structure of the Drosophila dosage compensation regulator Sex-lethal | journal = Genes & Development | volume = 26 | issue = 17 | pages = 1950–61 | date = September 2012 | pmid = 22922650 | doi = 10.1038/nature11416 | pmc = 3437099}} Sxl binds to both the 5' and 3' UTRs of *msl-2* mRNA. The binding in the 5' UTR leads to the retention of an intron containing a stop codon, while binding in both UTRs contributes to translational repression. This prevents the production of MSL-2 protein in females, thereby preventing dosage compensation from occurring.

Beyond *tra* and *msl-2*, Sxl has been shown to affect the expression of other genes. RIP-seq analysis has identified hundreds of potential Sxl targets in primordial germ cells, suggesting a broader role in gene regulation. Sxl also regulates gene expression by repressing translation, binding to both the 5' and 3'UTRs.

SXL contains an N-terminal Gly/Asn-rich domain that may be responsible for protein-protein interaction, and tandem RNA recognition motifs (RRMs) that show high preference for binding single-stranded, uridine-rich target RNA transcripts.{{cite journal | vauthors = Samuels M, Deshpande G, Schedl P | title = Activities of the Sex-lethal protein in RNA binding and protein:protein interactions | journal = Nucleic Acids Research | volume = 26 | issue = 11 | pages = 2625–37 | date = June 1998 | pmid = 9592147 | doi = 10.1093/nar/26.11.2625 | pmc = 147605 }} The crystal structure of the tandem RRMs bound to a *tra*-derived RNA reveals a V-shaped cleft where the RNA binds. Notably, there are no interdomain contacts between the RRMs in the absence of RNA, indicating conformational flexibility.{{cite journal | vauthors = Crowder SM, Kanaar R, Rio DC, Alber T | title = Absence of interdomain contacts in the crystal structure of the RNA recognition motifs of Sex-lethal | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 9 | pages = 4892–7 | date = April 1999 | pmid = 10220389 | doi = 10.1073/pnas.96.9.4892 | pmc = 21787 | bibcode = 1999PNAS...96.4892C | doi-access = free }}

• Sxl* homologs have been found in a wide range of insects, including other Diptera (flies), mosquitoes, butterflies, beetles, honeybees, ants, and aphids. However, the sex-determining function of Sxl appears to be specific to *Drosophila* and closely related species. Changes in the N- and C-termini of Sxl, rather than the RNA-binding region, are likely responsible for the evolution of its sex-determination function in *Drosophila*.

Sxl is known to interact with several other proteins, including:

• **U2AF:** Sxl antagonizes the binding of U2AF to the *tra* pre-mRNA.
• **PPS:** Sxl interacts with PPS, a large multidomain protein, which is required for *Sxl* autoregulation.{{cite journal | vauthors = Gebauer F, Grskovic M, Smibert CA, Harrison EJ, Hentze MW | title = Pervasive regulation of mRNA translation in Drosophila oocytes | journal = Molecular Cell | volume = 47 | issue = 1 | pages = 55–67 | date = July 2012 | pmid = 22683493 | doi = 10.1016/j.molcel.2012.05.037 | pmc = 3398326 }}
• **SNF (sans fille):** Sxl interacts with SNF, a U1 snRNP protein, in the regulation of *Sxl* splicing.
• **Sister of Sex-lethal (Ssx)**: Sxl and Ssx have comparable RNA-binding specificity, and compete for binding to RNA regulatory elements in the Sxl transcript.
• **eIF4E:** The translation initiation factor eIF4E has been shown to interact with Sxl and play a role in *msl-2* and *Sxl* splicing.

The name "Sex-lethal" derives from the fact that loss-of-function mutations are lethal in females (XX individuals) due to misregulation of dosage compensation. Some *Sxl* alleles cause female sterility rather than lethality. Conversely, gain-of-function *Sxl* alleles can be lethal in males. Mutations in *Sxl* can also affect sexual behavior and pheromone production. Somatic mosaic females that carry mutations in the *Sxl* gene develop abnormal genitalia and reproductive tissue.

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Category:Protein families

Category:Drosophila melanogaster genes

Category:RNA-binding proteins