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FB2026_01
,
released March 12, 2026
fs(1)M106, SxlPe, Sx1
RNA binding and splicing - the master regulation of sex determination in Drosophila - acts to control sex-specific gene regulation and sexual identity in both the germline and the soma, but acts as a general regulator of X chromosome gene expression and dosage compensation only in the soma
Please see the JBrowse view of Dmel\Sxl for information on other features
To submit a correction to a gene model please use the Contact FlyBase form
AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Some regions with low pLDDT may be unstructured in isolation.
Gene model reviewed during 6.02
Stop-codon suppression (UAA) postulated; FBrf0216884.
Annotated transcripts do not represent all possible combinations of alternative exons and/or alternative promoters
Gene model reviewed during 6.06
Gene model includes transcripts encoding non-overlapping portions of the full CDS.
Tissue-specific extension of 3' UTRs observed during later stages (FBrf0218523, FBrf0219848); all variants may not be annotated
Annotated transcripts do not represent all supported alternative splices within 5' UTR.
Gene model reviewed during 5.44
Gene model reviewed during 5.48
Gene model reviewed during 5.45
Gene model reviewed during 5.43
Gene model reviewed during 5.39
The group(s) of polypeptides indicated below share identical sequence to each other.
39 (kD)
43 (kD)
Part of a complex containing fl(2)d, Sxl and vir (PubMed:12444081). Part of a complex composed of at least mei-P26, bam, bgcn and Sxl; this complex is involved in translational repression of nanos mRNA (PubMed:23526974). interacts with mei-p26 (PubMed:23526974). Interacts with nito (PubMed:26324914). Interacts with Unr; cooperates with Unr to prevent translation of msl-2 transcripts (PubMed:16452508, PubMed:16452509, PubMed:18203923, PubMed:19941818, PubMed:25209665). Interacts with how; promoting nuclear retention of msl-2 transcripts (PubMed:23788626). Certain isoforms may interact with otu; the interaction may regulate sxl stability but does not require otu deubiquitinase activity (PubMed:40215271).
Click to get a list of regulatory features (enhancers, TFBS, etc.) and gene disruptions (point mutations, indels, etc.) within or overlapping Dmel\Sxl using the Feature Mapper tool.
The testis specificity index was calculated from modENCODE tissue expression data by Vedelek et al., 2018 to indicate the degree of testis enrichment compared to other tissues. Scores range from -2.52 (underrepresented) to 5.2 (very high testis bias).
Comment: XX pole cells
Comment: isoform encoding incomplete CDS
Sxl protein is detected in midgut cells of female, but not male, adults.
Sxl is expressed in female germline stem cells and in the adjacent two to three cells where the bam-898+133.GFP cyst cell marker is first expressed.
In region 3 of the germarium, Sxl can be seen in the oocyte and in all follicle cells, but is less expressed in polar and stalk cell precursors.
Sxl is normally expressed uniformly in female embryos starting from early blastoderm stages and is not expressed in male embryos. In hhb.P embryos, the ectopic h protein suppresses Sxl in the anterior of the embryo resulting in its expression only at the posterior end in female embryos. In schb.P embryos, ectopic sc protein causes ectopic Sxl expression in the anterior end of male embryos.
JBrowse - Visual display of RNA-Seq signals
View Dmel\Sxl in JBrowse1-19
1-20.4
Please Note FlyBase no longer curates genomic clone accessions so this list may not be complete
Please Note This section lists cDNAs and ESTs that fall within the genomic extent of the gene model, which may include cDNAs and ESTs of genes within introns, or of overlapping genes. Please see JBrowse for alignment of the cDNAs and ESTs to the gene model.
For each fully sequenced cDNA the DGRC maintains various forms of the cDNA (e.g tagged or untagged) in several different host vectors for subsequent cloning and expression in Drosophila and Drosophila cell lines.
Infection by Wolbachia restores fertility to D.melanogaster females that do not produce eggs because they have protein-coding lesions in Sxl. This suppression is allele specific.
Exon 3 repression in Sxl pre-mRNA splicing requires competition between the 5' splice sites of exons 2 and 3 but is independent of their relative strength. The distal 3' splice site preceeding exon 3 plays a critical role in defining the exon, while the proximal 3' splice site is preferentially used for the actual splicing reaction, suggesting a switch in 3' splice site recognition between the two processes of exon definition and splicing catalysis.
Recombination and disjunction in female germ cells depend on the germline activity of Sxl.
The crystal structure has been determined at 2.6A resolution of the complex formed between two tandemly arranged RNA-binding domains of the Sxl protein and a 12 nucleotide, single stranded RNA derived from the tra polypyrimidine tract. The two RNA-binding domains have their β-sheet platforms facing each other to form a V-shaped cleft. The RNA is bound in this cleft, where the tra UGUUUUUUU sequence is specifically recognized by the Sxl protein.
Candidate gene for sex comb tooth number and testicular atrophy quantitative trait loci.
Sxl acts as a translational repressor as well as a splicing regulator.
4.1kb, 3.1kb and 1.9kb transcript 3' UTRs contain 14, 8 and 1 consensus Rbp9 binding sites, respectively.
The two RRM (RNA recognition motif) domains of Sxl are responsible for RNA binding. Specificity in the recognition of target RNAs requires both RRM domains. The two RRM domains mediate Sxl :Sxl protein interactions, and these interactions probably occur both in cis and in trans. The interaction of Sxl protein with snf protein is mediated by the R1 RRM domain of Sxl.
Sxl has multiple and separable activities in the regulation of pre-mRNA splicing.
An increase in the dose of snf+ can trigger the female Sxl RNA splicing mode in male germ cells and can feminise triploid intersex (2X3A) germ cells. Female specific regulation of Sxl in the germline involves a position autoregulatory feedback loop on RNA splicing. Sxl-positive male germ cells make female Sxl protein isoforms. Somatic feminisation does not feminise Sxl-positive male germ cells.
The amino terminal RNA binding domain (RBD1) fragment of Sxl is prepared on the basis of a limited proteolysis analysis and the solution structure of RBD1 is determined by NMR. Analysis reveals RBD1 has non-consensus types of amino acid residues at several key positions near and inside the RNP2/RNP1 motifs.
The glycine-rich N-terminus of the Sxl protein influences interactions with hnRNP proteins containing RNA binding and glycine-rich domains.
The early (embryo) splicing pattern is not regulated by stage- or sex-specific trans-acting factors. The early splicing pattern is dependent on whether the 5' splice site region originates from exon E1 or exon 2.
Anti-Sxl monoclonal antibody detected Sxl-like proteins in species of the D.melanogaster and D.virilis radiation that migrate with the same size range as the two most prominent Sxl protein isoforms of D.melanogaster.
Male-specific lethal (MSL) proteins accumulate in a subregion of male nuclei (the X chromosome) beginning at late blastoderm stage. Binding of the MSLs is interdependent in diploid cells and is prevented in female embryonic cells by Sxl.
Reporter constructs used to examine the splicing of Sxl-Pe transcripts indicate that neither specific maternal products, Sxl protein, nor an X chromosome to autosome ratio of 1 are required for the processing of the embryonic mRNAs. Skipping two intervening exons to generate an open reading frame that will encode the Sxl early proteins appears to be an intrinsic property of initiating the early Sxl RNAs within the first intron of the Sxl-Pm maintenance transcription unit.
Molecular analysis of the SxlM alleles has been undertaken to address the question of what is responsible for their constitutive behavior. The constitutive character of the SxlM alleles is a consequence of an alteration of the structure of the pre-mRNA that allows some level of female splicing to occur even in the absence of functional Sxl gene product. Most of the constitutive character of SxlM alleles appears to depend on the mutant alleles' responsiveness, perhaps greater than wild type, to the autoregulatory splicing activity of the wild type Sxl proteins they produce.
In the early embryo the activity of Sxl-Pe is controlled in a highly dose-sensitive fashion by the genes on the X chromosome that function as denominator elements (sc, sisA, da and run). Functional dissection of Sxl-Pe indicates that activating the promoter in females requires the cumulative action of multiple numerator genes which appear to exert their effects through reiterated cis-acting target sites in the promoter. Conversely, maintaining the promoter silent in males requires the repressive activities of denominator genes, and at least one of the denominator genes also appears to function through target sequences within the promoter.
Female-specific expression of genes in the germline is dependent on a somatic signalling pathway whose primary target is not Sxl.
To initiate biophysical studies of the Sxl-polypyrimidine tract (PPT) complex minimal protein and RNA sequence elements have been identified that retain a specific high-affinity interaction.
Expression of Sxl recombinant genes demonstrate that neither RRM repeat alone can support strong specific Sxl RNA binding but two RRM repeats together with other N- and C-terminal sequences deleted binds RNA as tightly and specifically as the full length protein. The regions required for self interaction can now be identified using in vitro binding assays.
Female-specific functions of Sxl regulate sexual behaviour and synthesis of the three major sex pheromones that have been identified in normal sexually mature males and virgin females.
In vitro RNA binding has been used to demonstrate a cooperative interaction between the N-termini of two Sxl monomers when binding to adjacent U-rich binding sites on the Sxl pre-mRNA. Transient infections into Schneider cells and germline transformations also demonstrate the importance of the Sxl N-terminus.
Tumorous cells produced by Sxl mutants are capable of female-specific transcription and RNA processing indicating the ovarian cells retain some female identity. It is proposed that mutations do not cause male transformation of the female germ line but instead either cause an ambiguous sexual identity or block specific stages of oogenesis. Germ line function of Sxl depends on the activity of a specific otu isoform.
Resonance assignments and solution structure of a portion of Sxl containing the second RNA-binding domain has been determined using multidimensional heteronuclear NMR.
A fragment of the D.melanogaster Sxl gene has been used as a probe for in situ hybridisation of Chrysomya rufifacies polytene chromosomes.
RNA binding specificity of Sxl protein is examined by applying an in vitro selection and amplification of ligand RNAs from a random sequence pool. Sequence and in vitro binding analyses of the selected RNAs showed that Sxl preferentially binds to a polyuridine stretch surrounded by purine residues and the binding may be facilitated by an AG sequence downstream of the polyuridine stretch.
Sxl binds its own pre-mRNA at the 3' splice site of the male exon (exon 3) and at additional binding sites surrounding the male exon. The amino terminus of the Sxl protein has cooperative binding properties, this portion shares amino acid similarity with other RNA-binding proteins and is essential for Sxl's function as a splicing regulator in vivo.
Sex-specific processing of nascent Sxl RNA operates in the germ line as well as in the soma. One class of female sterile mutations is defective in germ-line sex-specific splicing of Sxl, another (including mutations at Sxl itself) is defective in the changes of Sxl protein distribution observed in wild type germ cells. During the final stages of oogenesis several mechanisms apparently operate to prevent progeny from inheriting Sxl protein.
sisA is required in all somatic nuclei for the proper activation of Sxl. Sxl is the only significant target of the somatic sex determination signal. An increased sisA dose equivalent to that in females causes male lethal effects and cannot activate the construct P{SxlPe-lacZ}, which carries the embryonic promoter of Sxl, to the female expression level in all tissues. Male lethality can be completely suppressed by a Sxl null mutation.
In females, the Sxl product functions to prevent mle from binding to the two X chromosomes.
In the soma, the sex of the cells is autonomously determined by the X:A signal, while in the germ line, the sex is determined by cell autonomous and somatic inductive signals. The genes sc, sisA, run are required to activate Sxl in the soma but not in the germ line. Transplantation studies support a somatic positive feminizing signal for germ-line development. Activation of Sxl in the germ line may be controlled by the X:A ratio and a positive feminizing signal from the soma.
Three exons and two introns around the regulated splice sites are sufficient for sex-specific splicing. The male exon 3' splice site is not the primary target for Sxl autoregulation, the 5' splice site of the male exon may be a target. Multiple upstream cis-acting elements are required for Sxl autoregulation.
The male Sxl exon is subject to Sxl regulation when a fragment containing the exon plus flanking intron sequences is placed in the introns of two different genes, ftz and w. A very small fragment of the male intron containing only the male intron plus 3' and 5' splice signals optimised to fit the consensus is sufficient for regulation in a heterologous context. The poly(U) run in the Sxl 3' splice site is also required for the sex-specific splicing. Results suggest a blockage mechanism is probably used in Sxl autoregulation, in support of Sosnowski et al (FBrf0049361).
A sequence comparison and numerical analysis of the RRM-containing (RNA recognition motif) proteins suggests that functionally related RRM-containing proteins have significant sequence similarities in their RRMs.
The region of the Sxl+ premRNA bearing the key regulatory stop codons is spliced in the same sex-specific manner in the germ line as in the soma. The genetic hierarchy regulating female germ-line sex determination includes tra, tra2, dsx, fu, otu, ovo, snf and Sxl itself. fu, otu, ovo and snf function upstream of Sxl.
Female cells may be viable in the absence of detectable Sxl protein expression.
Sxl function may not be sufficient to direct germ cells into the female pathway, and, in the germ line, Sxl may not be regulated by the X:A ratio.
In vitro system that recapitulates the regulation by Sxl of tra sex-specific splicing developed. Sxl blocks splicing to the non-sex specific, default site in tra by specifically binding to its polypyrimidine tract, blocking the binding of the essential splicing factor U2AF: U2AF then acivates the lower-affinity female-specific site. U2AF has a splicing effector domain that Sxl lacks: addition of this effector domain converts Sxl from a splicing repressor to a splicing activator, rendering it unable to mediate splice-site switching.
Cotransfection experiments in Kc cells show that the female-specific Sxl product induces the synthesis of its own female-specific mRNA by negative control of male-specific splicing. Deletion, substitution and binding experiments demonstrated that multiple uridine-rich sequences in the introns around the male-specific third exon are involved in the splicing regulation of Sxl pre-mRNA.
snf is a positive regulator of Sxl in the germline and soma.
Sxl function directs the development of sexually dimorphic skeletal muscles.
Dosage studies suggest balance of sc, dpn and Sxl involved in sex-specific lethality.
The sex-, stage-, and tissue-specific expression of Sxl protein has been determined.
Sxl promoter is uniquely sensitive to the dose of a small set of specific X/A numerator genes, including sisA and sc.
sc is a component of the X:A ratio and is required in females for the initiation of Sxl expression. Failure to activate Sxl expression in females results in lethality due to improper gene dosage compensation.
Dose-sensitive cooperative interactions in the assembly or binding of sis-dependent transcription factors may directly determine the activity of the female-specific promoter of Sxl.
Mutations in zygotic gene Sxl interact with RpII140wimp.
The structure of a number of late Sxl transcripts has been analysed.
Co-transfection experiments in which Sxl cDNA and the tra gene are expressed in Kc cells demonstrate that the female Sxl-encoded protein binds specifically to the tra transcript at or near the non-sex-specific acceptor site. This implies that the female Sxl gene product is the trans-acting factor that regulates alternative splicing.
da and sc are both required for the induction of Sxl expression.
The mechanism of sex determination in the germ line has been analysed.
The interaction between snf and Sxl mutations reduces the viability of females heterozygous for Sxl. The mosaicism exhibited by flies heterozygous for snf and Sxl- suggests that the transformation of diplo-X tissues to male morphology is due to the interaction of snf and Sxl in the zygote: failure to maintain Sxl expression in some somatic cells.
There is an interaction between snf and Sxl mutants indicating both gene products are involved in the regulation of the same pathway.
Genetic analysis of rearrangements within Sxl has allowed correlation of changes in specific functions with DNA alterations.
The X/A ratio is believed to act through an X-linked control gene, Sxl (Cline, 1978, Genetics 90, 683--698, Cline, 1983, Dev. Biol. 95, 260--274). High levels of Sxl expression dictate the female path of sexual differentiation and a low transcription rate for X-linked genes, low expression levels result in the male pathway and high levels of X-linked gene transcription (Cline, 1978, Genetics 90, 683--698, Cline, 1983, Dev. Biol. 95, 260--274). A model has been formulated on how the activity of the Sxl locus can be related to the X/A ratio (Gadagkar, 1982, J. Biosci.4, 377--390).
Sxl+ is a switch gene that acts throughout development to control all aspects of sexual dimorphism. Its products are required for female and must be absent for male development. Uniquely among sex-determination genes, after responding early in development to the primary sex-determination signal (the X:A ratio), Sxl maintains its own activity state as well as that of the downstream genes with which it interacts. It is required in a cell-autonomous fashion for both germ-line and somatic female development. It controls dosage compensation in females by suppressing hyperactivation of X-linked genes. Mutations of Sxl fall into two general classes: (1) recessive loss-of-function alleles that are deleterious to homozygous females, but viable and without phenotypic consequences in males, and (2) dominant gain-of-function alleles that behave as constitutive mutations, dominant and deleterious in males but without adverse effect in females, either heterozygous or homozygous. The variety of functions of the Sxl gene can be affected differentially by mutations, accounting in part for the complex complementation pattern observed for the large array of diverse mutant alleles. It is important to be aware that phenotypic parameters of mutant alleles and allele combinations can be very sensitive to culture conditions and genetic background. A number of positive regulators of Sxl are known, including the genes da, snf, sis-a and sis-b. The female-specific lethal or sterile effects of mutations in these genes are suppressed by gain-of-function Sxl alleles. Throughout all but the very earliest period of development, female-specific expression of Sxl is known to be achieved by female-specific splicing of mRNA. The translation products from these female-spliced RNAs appear to help maintain the female-specific (productive) RNA processing mode which generates them, thereby establishing a positive feedback loop that maintains the female state throughout development.
Source for merge of: Sxl CG18350
Source for merge of: Sxl CG14425
Annotations CG18350 and CG14425 merged as CG43770 in release 5.44 of the genome annotation. Merge supported by stop codon read-through analysis (FBrf0216884).
Dicistronic annotation CG33070 split out into separate annotations for each open reading frame, CG18350 and CG14425, in release 4.2 of the genome annotation. CG18350 corresponds to Sxl.
The current convention for this gene is that alleles specifically disrupting female development (generally recessive loss of function) are designated Sxlf, followed by a number, whereas those specifically disrupting male development (generally dominant gain of function) are designated "SxlM", followed by a number. In cases where a single lesion might have both characters, the "SxlM" designation would prevail. P in the designation indicates that the allele (and sometimes the stock as well) is likely to harbor P-element sequences. For new alleles selected as changes in the functioning of pre-existing mutant alleles, the original allele designation is followed by a d (for 'derivative'), then a number. If and when such derivatives are shown to carry more than one lesion within the gene, the mutant designation will change to reflect the presence and order on the chromosome of the multiple lesions, individual mutations being separated by commas. For the most part, alleles in common use before these conventions were adopted were renamed only if the changes were relatively minor and self evident.
