Sex-lethal
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| IPR006546 | |||||||
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| Symbol | Sxl | ||||||
| InterPro | IPR006546 | ||||||
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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.[1][2][3] 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.[3] It is most closely related to the ELAV/HUD subfamily of splicing factors.[4]
Mechanism of Action
[edit]In D. melanogaster, Sxl exerts its effects primarily through post-transcriptional regulation, specifically alternative splicing and translational repression.[3] It regulates at least three key target genes: *Sxl* itself (autoregulation), *transformer (tra)* (sex determination), and *male-specific lethal-2 (msl-2)* (dosage compensation).[3]
Autoregulation
[edit]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.[5][6] The protein PPS interacts with Sxl and helps mediate this effect.[7]
*transformer* Regulation
[edit]In fruit flies, Sxl protein participates in alternative splicing of the transformer gene, ultimately deciding the sex of the fly.[8] 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
[edit]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.[9][10] 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
[edit]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
[edit]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.[11] 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.[12]
Evolution
[edit]- 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*.
Protein Interactions
[edit]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.[7]
- **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.
Mutations and Phenotypes
[edit]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
[edit]- ↑ 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.
- ↑ 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.
- 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.