Sex-lethal

IPR006546
Identifiers
SymbolSxl
InterProIPR006546
Available protein structures:
PDB  IPR006546  
AlphaFold
Alternative splicing of the Drosophila Transformer gene product.

Sex-lethal (Sxl) is the master regulatory gene for both sex determination and dosage compensation in Drosophila melanogaster (P19339), where it functions as an RNA-binding protein. Named for its mutation phenotype in D. melanogaster, Sxl is found in Dipteran insects. Though present in both sexes, Sxl's activity is female-specific in D. melanogaster. It is most closely related to the ELAV/HUD subfamily of splicing factors.

Mechanism of Action

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).

Autoregulation

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. The protein PPS interacts with Sxl and helps mediate this effect.

*transformer* Regulation

In fruit flies, Sxl protein participates in alternative splicing of the transformer gene, ultimately deciding the sex of the fly. 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.

*msl-2* Regulation

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. 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.

Additional Targets and Translational Control

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.

Protein Structure

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. 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.

Evolution

Protein Interactions

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

Mutations and Phenotypes

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.

References

  1. ↑ Maine EM, Salz HK, Cline TW, Schedl P (December 1985). "The Sex-lethal gene of Drosophila: DNA alterations associated with sex-specific lethal mutations". Cell. 43 (2 Pt 1): 521–9. doi:10.1016/0092-8674(85)90181-3. PMID 3000609. S2CID 32594881.
  2. ↑ Meise M, Hilfiker-Kleiner D, Dübendorfer A, Brunner C, Nöthiger R, Bopp D (April 1998). "Sex-lethal, the master sex-determining gene in Drosophila, is not sex-specifically regulated in Musca domestica" (PDF). Development. 125 (8): 1487–94. doi:10.1242/dev.125.8.1487. PMID 9502729.
  3. 1 2 3 4 Penalva LO, Sánchez L (September 2003). "RNA binding protein sex-lethal (Sxl) and control of Drosophila sex determination and dosage compensation". Microbiology and Molecular Biology Reviews. 67 (3): 343–59, table of contents. doi:10.1128/mmbr.67.3.343-359.2003. PMC 193869. PMID 12966139.
  4. ↑ Schütt C, Nöthiger R (February 2000). "Structure, function and evolution of sex-determining systems in Dipteran insects". Development. 127 (4): 667–77. doi:10.1242/dev.127.4.667. PMID 10648226.
  5. ↑ Horabin JI, Emmons AT, VanVickle-Chavez SJ, Chen T (February 2015). "Distinct regulatory steps in the Drosophila sex determination pathway use Sex-lethal to exert analog control". Genetics. 199 (2): 509–23. doi:10.1016/j.cell.2015.01.013. PMC 4349088. PMID 25635454.
  6. ↑ Klein ME, Moursi A, Mer G, Rio DC (July 2020). "Mechanism of regulated alternative 5' splice site selection by Drosophila Sex-lethal". Proceedings of the National Academy of Sciences of the United States of America. 117 (27): 15721–15731. Bibcode:2020PNAS..11715721K. doi:10.1016/j.fm.2020.103532. PMC 7345674. PMID 32539959.
  7. 1 2 Gebauer F, Grskovic M, Smibert CA, Harrison EJ, Hentze MW (July 2012). "Pervasive regulation of mRNA translation in Drosophila oocytes". Molecular Cell. 47 (1): 55–67. doi:10.1016/j.molcel.2012.05.037. PMC 3398326. PMID 22683493.
  8. ↑ Bell LR, Maine EM, Schedl P, Cline TW (December 1988). "Sex-lethal, a Drosophila sex determination switch gene, exhibits sex-specific RNA splicing and sequence similarity to RNA binding proteins". Cell. 55 (6): 1037–46. doi:10.1016/0092-8674(88)90248-6. PMID 3144435. S2CID 22691059.
  9. ↑ Kelley RL, Wang J, Bell L, Kuroda MI (October 1995). "Sex-lethal controls dosage compensation in Drosophila by a non-splicing mechanism". Nature. 377 (6548): 428–31. Bibcode:1995Natur.377..428K. doi:10.1038/377428a0. PMID 7566118. S2CID 4292579.
  10. ↑ Merz J, Ghosh S, Bellini D, Pipalia T, Shcherbakova I, Huang SC, Gehring NH, Hiller M, Kaygun H, Zavolan M, Ghosh G (September 2012). "Molecular mechanism and structure of the Drosophila dosage compensation regulator Sex-lethal". Genes & Development. 26 (17): 1950–61. doi:10.1038/nature11416. PMC 3437099. PMID 22922650.
  11. ↑ Samuels M, Deshpande G, Schedl P (June 1998). "Activities of the Sex-lethal protein in RNA binding and protein:protein interactions". Nucleic Acids Research. 26 (11): 2625–37. doi:10.1093/nar/26.11.2625. PMC 147605. PMID 9592147.
  12. ↑ Crowder SM, Kanaar R, Rio DC, Alber T (April 1999). "Absence of interdomain contacts in the crystal structure of the RNA recognition motifs of Sex-lethal". Proceedings of the National Academy of Sciences of the United States of America. 96 (9): 4892–7. Bibcode:1999PNAS...96.4892C. doi:10.1073/pnas.96.9.4892. PMC 21787. PMID 10220389.
This article incorporates text from the public domain Pfam and InterPro: IPR006546