Sex-lethal

Last updated
IPR006546
Identifiers
SymbolSxl
InterPro IPR006546
Alternative splicing of the Drosophila Transformer gene product. Transformer splicing.gif
Alternative splicing of the DrosophilaTransformer 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. [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]

Contents

Mechanism of Action

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

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

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

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

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. [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

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:10.1534/genetics.114.172883. 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:10.1073/pnas.2004022117. 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:10.1101/gad.196981.112. 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
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.