scholarly journals VITAL GENES THAT FLANK SEX-LETHAL, AN X-LINKED SEX-DETERMINING GENE OF DROSOPHILA MELANOGASTER

Genetics ◽  
1983 ◽  
Vol 103 (4) ◽  
pp. 617-631
Author(s):  
Janice A Nicklas ◽  
Thomas W Cline
Keyword(s):  
Relative Sensitivity ◽  
X Rays ◽  
Loss Of Function ◽  
Induced Mutations ◽  
Salivary Gland Polytene Chromosome ◽  
Complementation Groups ◽  
Sex Lethal ◽  
Female Specific ◽  
Male Specific ◽  
Relationship Of

ABSTRACT The X-chromosome:autosome balance in D. melanogaster appears to control both sex determination and dosage compensation through effects on a maternally influenced sex-linked gene called Sex-lethal (Sxl; 1-19.2). To facilitate molecular and genetic analysis of Sxl, we attempted to determine the locations of all ethyl methanesulfonate (EMS)-mutable genes vital to both sexes in the region between 6E1 and 7B1. This area includes approximately 1 cM of the genetic map on each side of Sxl and was reported by C. B. Bridges to contain 26 salivary gland polytene chromosome bands. The region appears rather sparsely populated with genes vital to both sexes, since the 122 recessive lethal mutations we recovered fell into only nine complementation groups. From one to 38 alleles of each gene were recovered. There was a preponderance of embryonic lethals in this area, although the lethal periods of loss-of-function mutations included larval, pupal and adult stages as well. Since the screen required that mutations be recessive and lethal to males, our failure to recover new Sxl alleles was the result expected for a gene with a female-specific function. An attempt was made to identify recessive male-specific lethals in this region, but none were found. Precise map positions were determined for eight of the nine vital genes. An interesting feature of the map is the location of Sxl in the middle of a 0.6- to 0.7-cM interval that appears to be devoid of genes vital to both sexes. The genetic location was determined of breakpoints near Sxl for all available chromosome rearrangements. Sxl is most likely located just to the left of band 7A1. We determined the relationship of our EMS-induced mutations in these nine genes to alleles induced by others. From this we conclude that the various genes appear to differ significantly from each other in their relative sensitivity to mutation by EMS vs. X rays.

scholarly journals Both Loss-of-Function and Gain-of-Function Mutations in snf Define a Role for snRNP Proteins in Regulating Sex-lethal Pre-mRNA Splicing in Drosophila Development

Genetics ◽  
1996 ◽  
Vol 144 (1) ◽  
pp. 95-108
Author(s):  
Helen K Salz ◽  
Thomas W Flickinger
Keyword(s):  
Sex Determination ◽  
Rna Splicing ◽  
Loss Of Function ◽  
Functional Homology ◽  
Snrnp Protein ◽  
A Cell ◽  
Sex Lethal ◽  
Mutant Phenotypes ◽  
Female Specific ◽  
Male Specific

Abstract The Drosophila snf gene encodes a protein with functional homology to the mammalian UlA and U2B″ snRNP proteins. Studies, based on the analysis of three viable alleles, have suggested a role for snf in establishing the female-specific splicing pattern of the sex determination switch gene, Sex-lethal. Here, we show that the non-sex-specific lethal null allele is required for female sex determination, arguing against the formal possibility that the viable alleles disrupt a function unrelated to snf's wild-type function. Moreover, we find snf is required for normal cell growth and/or survival, as expected for a protein involved in a cell-vital process such as RNA splicing. We also show that of the three viable alleles only one, snfJA2, is a partial loss-of-function mutation. The other two viable alleles, snf1621 and snfe8H, encode antimorphic proteins. We find the antimorphic proteins are mislocalized and correlate their mislocalization with their molecular lesions and mutant phenotypes. Finally, we provide genetic evidence that the antimorphic alleles interfere with the autoregulatory splicing function of the Sex-lethal protein. Based on these studies we suggest a model in which the snRNP protein, Snf, functions with Sex-lethal to block recognition of the regulated male-specific exon.

scholarly journals TWO CLOSELY LINKED MUTATIONS IN DROSOPHILA MELANOGASTER THAT ARE LETHAL TO OPPOSITE SEXES AND INTERACT WITH DAUGHTERLESS

Genetics ◽  
1978 ◽  
Vol 90 (4) ◽  
pp. 683-697
Author(s):  
Thomas W Cline
Keyword(s):  
Maternal Effect ◽  
Spontaneous Mutation ◽  
Dominant Male ◽  
Lethal Effects ◽  
Male Specific Lethal ◽  
Constitutive Mutation ◽  
Sex Lethal ◽  
The Right ◽  
Female Specific ◽  
Male Specific

ABSTRACT A new spontaneous mutation named Sex-lethal, Male-specific #1 (SxlM1) is described that is lethal to males, even in the presence of an Sxl  + duplication. Females homozygous for SxlM1 are fully viable. This dominant, male-specific lethal mutation is on the X chromosome approximately 0.007 map units to the right of a previously isolated female-specific mutation, Female-lethal, here renamed Sex-lethal, Female-specific #1 (SxlF1). SxlM1 and SxlF1 are opposite in nearly every respect, particularly with regard to their interaction with the maternal effect of the autosomal mutation, daughterless (da). Females that are homozygous for da produce defective eggs that cannot support female (XX) development. A single dose of SxlM1 enables daughters to survive this da female-specific lethal maternal effect. A duplication of the Sxl locus weakly mimics this action of SxlM1. In contrast, SxlF1 and a deficiency for Sxl, strongly enhance the female-lethal effects of da. The actions of SxlM1 and SxlF1 are explained by a model in which expression of the Sxl locus is essential for females, lethal for males, and under the control of a product of the da locus. It is suggested that SxlM1 is a constitutive mutation at the Sxl locus.

flex, an X-linked female-lethal mutation in Drosophila melanogaster controls the expression of Sex-lethal

Development ◽  
1999 ◽  
Vol 126 (23) ◽  
pp. 5485-5493 ◽  
Author(s):  
A. Bhattacharya ◽  
S. Sudha ◽  
H.S. Chandra ◽  
R. Steward
Keyword(s):  
Genetic Interaction ◽  
Lethal Mutation ◽  
Mode Analysis ◽  
Loss Of Function ◽  
Splicing Regulators ◽  
Egg Chambers ◽  
Sex Lethal ◽  
The Stability ◽  
Male Specific ◽  
New Alleles

The Sex-lethal (Sxl) gene is required in Drosophila females for sexual differentiation of the soma, for gem cell differentiation and dosage compensation. We have isolated three new alleles of female-lethal-on-X (flex), an X-linked female-lethal mutation and have characterized its function in sex determination. SXL protein is missing in flex/flex embryos, however transcription from both Sxl(Pe), the early Sxl promoter and Sxl(Pm), the late maintenance promoter, is normal in flex homozygotes. In flex/flex embryos, Sxl mRNA is spliced in the male mode. Analysis of flex germline clones shows that it also functions in oogenesis, but in contrast to Sxl mutants that show an early arrest tumorous phenotype, flex mutant egg chambers develop to stage 10. In flex ovarian clones, Sxl RNA is also spliced in the male form. Hence, flex is a sex-specific regulator of Sxl functioning in both the soma and the germline. Genetic interaction studies show that flex does not enhance female lethality of Sxl loss-of-function alleles but it rescues the male-specific lethality of both of the gain-of-function Sxl mutations, Sxl(M1)and Sxl(M4.) In contrast to mutations in splicing regulators of Sxl, the female lethality of flex is not rescued by either Sxl(M1)or Sxl(M4). Based on these observations, we propose that flex regulates Sxl at a post-splicing stage and regulates either its translation or the stability of the SXL protein.

scholarly journals The Nab2 RNA binding protein promotes sex-specific splicing of Sex lethal in Drosophila neuronal tissue

2020 ◽  
Author(s):  
Binta Jalloh ◽  
J. Christopher Rounds ◽  
Brianna E. Brown ◽  
Isaac J. Kremsky ◽  
Ayan Banerjee ◽  
...  
Keyword(s):  
Rna Binding ◽  
Molecular Level ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Neuronal Tissue ◽  
Multiple Phenotypes ◽  
Axon Projection ◽  
Sex Lethal ◽  
Female Specific ◽  
Male Specific

AbstractThe Drosophila polyadenosine RNA binding protein Nab2, which is orthologous to a human protein lost in a form of inherited intellectual disability, controls axon projection, locomotion, and memory. Here we define an unexpectedly specific role for Nab2 in regulating splicing of ~150 exons/introns in the head transcriptome and link the most prominent of these, female retention of a male-specific exon in the sex determination factor Sex-lethal (Sxl), to a role in m6A-dependent mRNA splicing. Genetic evidence indicates that aberrant Sxl splicing underlies multiple phenotypes in Nab2 mutant females. At a molecular level, Nab2 associates with Sxl pre-mRNA and ensures proper female-specific splicing by preventing m6A hypermethylation by Mettl3 methyltransferase. Consistent with these results, reducing Mettl3 expression rescues developmental, behavioral and neuroanatomical phenotypes in Nab2 mutants. Overall these data identify Nab2 as a required regulator of m6A-regulated Sxl splicing and imply a broad link between Nab2 and Mettl3-regulated brain RNAs.

AUTOREGULATORY FUNCTIONING OF A DROSOPHILA GENE PRODUCT THAT ESTABLISHES AND MAINTAINS THE SEXUALLY DETERMINED STATE

Genetics ◽  
1984 ◽  
Vol 107 (2) ◽  
pp. 231-277
Author(s):  
Thomas W Cline
Keyword(s):  
Sex Determination ◽  
Dosage Compensation ◽  
Cellular Response ◽  
Regulatory Gene ◽  
Activity Level ◽  
Loss Of Function ◽  
Lethal Effects ◽  
Epigenetic Effect ◽  
Female Specific ◽  
Male Specific

ABSTRACT Sxl appears to head a regulatory gene hierarchy that controls Drosophila sexual dimorphism in response to the X chromosome/autosome balance. Only XXAA cells normally have Sxl  + activity. It maintains both the female morphogenetic sequence and a level of X-linked dosage-compensated gene expression compatible with diplo-X cell survival. In the absence of this activity, male sexual development and dosage-compensated gene hyperactivation ensure. Loss-of-function Sxl mutations generally have female-specific lethal effects caused by upsets in dosage compensation. New female-viable Sxl mutant alleles and combinations which lack Sxl's female sex determination function, yet still provide sufficient dosage compensation function for diplo-X survival, are described here. Consequently, such mutants cause genotypic females to develop as phenotypic males. Some of these sex-transforming Sxl mutants do not require the maternally produced da  + activity that is normally essential for the functioning of zygotic Sxl alleles. In this paper, products of these unusual alleles are shown to act in trans to induce the expression of zygotic Sxl  + alleles that would otherwise be unable to function due to a lack of maternal da  + activity. This result indicates a third function for Sxl  + product: a positive autoregulatory role. Controls for the autoregulation experiments demonstrated the sex-trans-forming epigenetic effect of the da mutation for the first time in diploids. In these experiments the female-specific zygotic lethal effects that normally would have accompanied loss of maternal da  + activity were suppressed by mutations known to block dosage-compensation gene hyperactivation-the autosomal, male-specific lethals. Three types of abnormal sexual phenotypes were produced in the experiments described here, each with important implications for the mechanism of sex determination: (1) a true intersex phenotype produced by one particular Sxl allele shows that Sxl  + must be involved in the cellular response to the X/A balance rather than in its establishment; (2) a maternally induced, female-sterile phenotype indicates that either the process of autoregulation or the mutants used to demonstrate it are tissue specific and (3) a mosaic intersexual phenotype whose character implies that the Sxl  + activity level is set early in development, both by the da  +-mediated X/A balance signal and by autoregulation, and is maintained subsequently in a cell autonomous fashion, independent of the initiating X/A balance signal. Thus, this study supports the view that sex determination is truly determinative in the standard developmental sense, and that Sxl is the carrier of the sexually determined state.

scholarly journals INCREASED SPONTANEOUS MITOTIC SEGREGATION IN MMS-SENSITIVE MUTANTS OF SACCHAROMYCES CEREVISIAE

Genetics ◽  
1977 ◽  
Vol 87 (2) ◽  
pp. 229-236
Author(s):  
Satya Prakash ◽  
Louise Prakash
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Methyl Methanesulfonate ◽  
X Rays ◽  
X Ray ◽  
Complementation Groups

ABSTRACT Methyl methanesulfonate (MMS)-sensitive mutants of Saccharomyces cerevisiae belonging to four different complementation groups, when homozygous, increase the rate of spontaneous mitotic segregation to canavanine resistance from heterozygous sensitive (canr/+) diploids by 13- to 170-fold. The mms8—1 mutant is MMS and X-ray sensitive and increases the rate of spontaneous mitotic segregation 170-fold. The mms9—1 and mms13—1 mutants are sensitive to X rays and UV, respectively, in addition to MMS, and increase the rate of spontaneous mitotic segregation by 13-fold and 85-fold, respectively. The mutant mms21—1 is sensitive to MMS, X rays and UV and increases the rate of spontaneous mitotic segregation 23-fold.

scholarly journals Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression

Blood ◽  
2011 ◽  
Vol 118 (19) ◽  
pp. 5278-5282 ◽  
Author(s):  
Victor R. Gordeuk ◽  
Galina Y. Miasnikova ◽  
Adelina I. Sergueeva ◽  
Xiaomei Niu ◽  
Mehdi Nouraie ◽  
...  
Keyword(s):  
Geometric Mean ◽  
Cell Mass ◽  
Hypoxia Inducible Factor ◽  
Loss Of Function ◽  
Ferritin Concentration ◽  
Hepcidin Expression ◽  
Serum Ferritin Concentration ◽  
Serum Hepcidin ◽  
Relationship Of ◽  
Serum Erythropoietin

Abstract Hypoxia is known to reduce the expression of hepcidin, the master regulator of iron metabolism. However, it is not clear whether this response is primarily related to increased erythropoiesis driven by hypoxically stimulated erythropoietin or to a more direct effect of hypoxia on hepcidin expression. The germline loss-of-function VHLR200W mutation is common in Chuvashia, Russia, and also occurs elsewhere. VHLR200W homozygotes have elevated hypoxia-inducible factor 1α (HIF-1α) and HIF-2α levels, increased red cell mass, propensity to thrombosis, and early mortality. Ninety VHLR200W homozygotes and 52 controls with normal VHL alleles from Chuvashia, Russia, were studied under basal circumstances. In univariate analyses, serum hepcidin concentration was correlated positively with serum ferritin concentration and negatively with homozygosity for VHLR200W. After adjustment for serum erythropoietin and ferritin concentrations by multiple linear regression, the geometric mean (95% confidence interval of mean) hepcidin concentration was 8.1 (6.3-10.5) ng/mL in VHLR200W homozygotes versus 26.9 (18.6-38.0) ng/mL in controls (P < .001). In contrast, a significant independent relationship of serum erythropoietin, hemoglobin, or RBC count with hepcidin was not observed. In conclusion, up-regulation of the hypoxic response leads to decreased expression of hepcidin that may be independent of increased erythropoietin levels and increased RBC counts.

Induction of female Sex-lethal RNA splicing in male germ cells: implications for Drosophila germline sex determination

Development ◽  
1997 ◽  
Vol 124 (24) ◽  
pp. 5033-5048 ◽  
Author(s):  
J.H. Hager ◽  
T.W. Cline
Keyword(s):  
Sex Determination ◽  
Germ Cells ◽  
Rna Splicing ◽  
Feedback Loop ◽  
Dose Effect ◽  
Male Germ Cells ◽  
Control Female ◽  
Sex Lethal ◽  
Specific Regulation ◽  
Female Specific

With a focus on Sex-lethal (Sxl), the master regulator of Drosophila somatic sex determination, we compare the sex determination mechanism that operates in the germline with that in the soma. In both cell types, Sxl is functional in females (2X2A) and nonfunctional in males (1X2A). Somatic cell sex is determined initially by a dose effect of X:A numerator genes on Sxl transcription. Once initiated, the active state of SXL is maintained by a positive autoregulatory feedback loop in which Sxl protein insures its continued synthesis by binding to Sxl pre-mRNA and thereby imposing the productive (female) splicing mode. The gene splicing-necessary factor (snf), which encodes a component of U1 and U2 snRNPs, participates in this RNA splicing control. Here we show that an increase in the dose of snf+ can trigger the female Sxl RNA splicing mode in male germ cells and can feminize triploid intersex (2X3A) germ cells. These snf+ dose effects are as dramatic as those of X:A numerator genes on Sxl in the soma and qualify snf as a numerator element of the X:A signal for Sxl in the germline. We also show that female-specific regulation of Sxl in the germline involves a positive autoregulatory feedback loop on RNA splicing, as it does in the soma. Neither a phenotypically female gonadal soma nor a female dose of X chromosomes in the germline is essential for the operation of this feedback loop, although a female X-chromosome dose in the germline may facilitate it. Engagement of the Sxl splicing feedback loop in somatic cells invariably imposes female development. In contrast, engagement of the Sxl feedback loop in male germ cells does not invariably disrupt spermatogenesis; nevertheless, it is premature to conclude that Sxl is not a switch gene in germ cells for at least some sex-specific aspects of their differentiation. Ironically, the testis may be an excellent organ in which to study the interactions among regulatory genes such as Sxl, snf, ovo and otu which control female-specific processes in the ovary.

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