From head to toes: the multiple facets of Sox proteins.
Sox proteins belong to the HMG box superfamily of DNA-binding proteins and are found throughout the animal kingdom. They are involved in the regulation of such diverse developmental processes as germ layer formation, organ development and cell type specifi-cation. Hence, deletion or mutation of Sox proteins often results in developmental defects and congenital disease in humans. Sox proteins perform their function in a complex interplay with other transcription factors in a manner highly dependent on cell type and promoter context. They exhibit a remarkable crosstalk and functional redundancy among each other. (+info)
An N-terminal truncation uncouples the sex-transforming and dosage compensation functions of sex-lethal.
In Drosophila melanogaster, Sex-lethal (Sxl) controls autoregulation and sexual differentiation by alternative splicing but regulates dosage compensation by translational repression. To elucidate how Sxl functions in splicing and translational regulation, we have ectopically expressed a full-length Sxl protein (Sx.FL) and a protein lacking the N-terminal 40 amino acids (Sx-N). The Sx.FL protein recapitulates the activity of Sxl gain-of-function mutations, as it is both sex transforming and lethal in males. In contrast, the Sx-N protein unlinks the sex-transforming and male-lethal effects of Sxl. The Sx-N proteins are compromised in splicing functions required for sexual differentiation, displaying only partial autoregulatory activity and almost no sex-transforming activity. On the other hand, the Sx-N protein does retain substantial dosage compensation function and kills males almost as effectively as the Sx.FL protein. In the course of our analysis of the Sx.FL and Sx-N transgenes, we have also uncovered a novel, negative autoregulatory activity, in which Sxl proteins bind to the 3' untranslated region of Sxl mRNAs and decrease Sxl protein expression. This negative autoregulatory activity may be a homeostasis mechanism. (+info)
An apparent excess of sex- and reproduction-related genes on the human X chromosome.
We describe here the results of a search of Mendelian inheritance in man, GENDIAG and other sources which suggest that, in comparison with autosomes 1, 2, 3, 4 and 11, the X chromosome may contain a significantly higher number of sex- and reproduction-related (SRR) genes. A similar comparison between X-linked entries and a subset of randomly chosen entries from the remaining autosomes also indicates an excess of genes on the X chromosome with one or more mutations affecting sex determination (e.g. DAX1), sexual differentiation (e.g. androgen receptor) or reproduction (e.g. POF1). A possible reason for disproportionate occurrence of such genes on the X chromosome could be that, during evolution, the 'choice' of a particular pair of homomorphic chromosomes for specialization as sex chromosomes may be related to the number of such genes initially present in it or, since sex determination and sexual dimorphism are often gene dose-dependent processes, the number of such genes necessary to be regulated in a dose-dependent manner. Further analysis of these data shows that XAR, the region which has been added on to the short arm of the X chromosome subsequent to eutherian-marsupial divergence, has nearly as high a proportion of SRR genes as XCR, the conserved region of the X chromosome. These observations are consistent with current hypotheses on the evolution of sexually antagonistic traits on sex chromosomes and suggest that both XCR and XAR may have accumulated SRR traits relatively rapidly because of X linkage. (+info)
The Drosophila gene stand still encodes a germline chromatin-associated protein that controls the transcription of the ovarian tumor gene.
The Drosophila gene stand still (stil) encodes a novel protein required for survival, sexual identity and differentiation of female germ cells. Using specific antibodies, we show that the Stil protein accumulates in the nucleus of all female germ cells throughout development, and is transiently expressed during early stages of male germline differentiation. Changes of Stil subnuclear localization during oogenesis suggest an association with chromatin. Several mutant alleles, which are point mutations in the Stil N-terminal domain, encode proteins that no longer co-localized with chromatin. We find that Stil binds to many sites on polytene chromosomes with strong preference for decondensed chromatin. This localization is very similar to that of RNA polymerase II. We show that Stil is required for high levels of transcription of the ovarian tumor gene in germ cells. Expression of ovarian tumor in somatic cells can be induced by ectopic expression of Stil. Finally, we find that transient ubiquitous somatic expression of Stil results in lethality of the fly at all stages of development. (+info)
A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators.
Deletion of the distal short arm of chromosome 9 (9p) has been reported in a number of cases to be associated with gonadal dysgenesis and XY sex reversal, suggesting that this region contains one or more genes required in two copies for normal testis development. Recent studies have greatly narrowed the interval containing this putative autosomal testis-determining gene(s) to the distal portion of 9p24.3. We previously identified DMRT1, a human gene with sequence similarity to genes that regulate the sexual development of nematodes and insects. These genes contain a novel DNA-binding domain, which we named the DM domain. DMRT1 maps to 9p24. 3 and in adults is expressed specifically in the testis. We have investigated the possible role of DM domain genes in 9p sex reversal. We identified a second DM domain gene, DMRT2, which also maps to 9p24.3. We found that point mutations in the coding region of DMRT1 and the DM domain of DMRT2 are not frequent in XY females. We showed by fluorescence in situ hybridization analysis that both genes are deleted in the smallest reported sex-reversing 9p deletion, suggesting that gonadal dysgenesis in 9p-deleted individuals might be due to combined hemizygosity of DMRT1 and DMRT2. (+info)
Negative regulation of male development in Caenorhabditis elegans by a protein-protein interaction between TRA-2A and FEM-3.
The tra-2 gene of the nematode Caenorhabditis elegans encodes a predicted membrane protein, TRA-2A, that promotes XX hermaphrodite development. Genetic analysis suggests that tra-2 is a negative regulator of three genes that are required for male development: fem-1, fem-2, and fem-3. We report that the carboxy-terminal region of TRA-2A interacts specifically with FEM-3 in the yeast two-hybrid system and in vitro. Consistent with the idea that FEM-3 is a target of negative regulation, we find that excess FEM-3 can overcome the feminizing effect of tra-2 and cause widespread masculinization of XX somatic tissues. In turn, we show that the masculinizing effects of excess FEM-3 can be suppressed by overproduction of the carboxy-terminal domain of TRA-2A. A FEM-3 fragment that retains TRA-2A-binding activity can masculinize fem-3(+) animals, but not fem-3 mutants, suggesting that it is possible to release and to activate endogenous FEM-3 by titrating TRA-2A. We propose that TRA-2A prevents male development by interacting directly with FEM-3 and that a balance between the opposing activities of TRA-2A and FEM-3 determines sex-specific cell fates in somatic tissues. When the balance favors FEM-3, it acts through or with the other FEM proteins to promote male cell fates. (+info)
Virilization of the male pouch young of the tammar wallaby does not appear to be mediated by plasma testosterone or dihydrotestosterone.
Virilization of the male urogenital tract of all mammals, including marsupials, is mediated by androgenic hormones secreted by the testes. We have previously demonstrated profound sexual dimorphism in the concentrations of gonadal androgens in pouch young of the tammar wallaby Macropus eugenii during the interval when the urogenital sinus virilizes. To provide insight into the mechanisms by which androgens are transported from the testes to the target tissues, we measured testosterone and dihydrotestosterone in plasma pools from tammar pouch young from the day of birth to Day 150. Plasma testosterone levels were measurable (0.5-2 ng/ml) at all times studied, but there were no differences between males and females. These low concentrations of plasma testosterone appear to be derived from the adrenal glands and not the testes. Plasma dihydrotestosterone levels in plasma pools from these animals were also low and not sexually dimorphic. We conclude that virilization of the male urogenital tract cannot be explained by the usual transport of testosterone or dihydrotestosterone in plasma but may be mediated by the direct delivery of androgens to the urogenital tract via the Wolffian ducts. Alternatively, circulating prohormones may be converted to androgens in target tissues. (+info)
Analysis of the doublesex female protein in Drosophila melanogaster: role on sexual differentiation and behavior and dependence on intersex.
doublesex (dsx) is unusual among the known sex-determination genes of Drosophila melanogaster in that functional homologs are found in distantly related species. In flies, dsx occupies a position near the bottom of the sex determination hierarchy. It is expressed in male- and female-specific forms and these proteins function as sex-specific transcription factors. In the studies reported here, we have ectopically expressed the female Dsx protein (Dsx(F)) from a constitutive promoter and examined its regulatory activities independent of other upstream factors involved in female sex determination. We show that it functions as a positive regulator of female differentiation and a negative regulator of male differentiation. As predicted by the DNA-binding properties of the Dsx protein, Dsx(F) and Dsx(M) compete with each other for the regulation of target genes. In addition to directing sex-specific differentiation, Dsx(F) plays an important role in sexual behavior. Wild-type males ectopically expressing Dsx(F) are actively courted by other males. This acquisition of feminine sex appeal is likely due to the induction of female pheromones by Dsx(F). More extreme behavioral abnormalities are observed when Dsx(F) is ectopically expressed in dsx(-) XY animals; these animals are not only courted by, but also copulate with, wild-type males. Finally, we provide evidence that intersex is required for the feminizing activities of Dsx(F) and that it is not regulated by the sex-specific splicing cascade. (+info)