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intersex, a gene required for female sexual development in Drosophila, is expressed in both sexes and functions together with doublesex to regulate terminal differentiation.

Previous genetic studies indicated intersex (ix) functions only in females and that it acts near the end of the sex determination hierarchy to control somatic sexual differentiation in Drosophila melanogaster. We have cloned ix and characterized its function genetically, molecularly and biochemically. The ix pre-mRNA is not spliced, and ix mRNA is produced in both sexes. The ix gene encodes a 188 amino acid protein, which has a sequence similar to mammalian proteins thought to function as transcriptional activators, and a Caenorhabditis elegans protein that is thought to function as a transcription factor. Bringing together the facts that (1) the ix phenotype is female-specific and (2) functions at the end of the sex determination hierarchy, yet (3) is expressed sex non-specifically and appears likely to encode a transcription factor with no known DNA-binding domain, leads to the inference that ix may require the female-specific protein product of the doublesex (dsx) gene in order to function. Consistent with this inference, we find that for all sexually dimorphic cuticular structures examined, ix and dsx are dependent on each other to promote female differentiation. This dependent relationship also holds for the only known direct target of dsx, the Yolk protein (Yp) genes. Using yeast 2-hybrid assay, immunoprecipitation of recombinant tagged IX and DSX proteins from Drosophila S2 cell extracts, and gel shifts with the tagged IX and DSX(F) proteins, we demonstrate that IX interacts with DSX(F), but not DSX(M). Taken together, the above findings strongly suggest that IX and DSX(F) function in a complex, in which IX acts as a transcriptional co-factor for the DNA-binding DSX(F).

Alternative Splicing↗

Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice.

To study further the role of gonadotropins in reproductive functions, we generated mice with LH receptor (LHR) knockout (LuRKO) by inactivating, through homologous recombination, exon 11 on the LHR gene. LuRKO males and females were born phenotypically normal, with testes, ovaries, and genital structures indistinguishable from their wild-type (WT) littermates. Postnatally, testicular growth and descent, and external genital and accessory sex organ maturation, were blocked in LuRKO males, and their spermatogenesis was arrested at the round spermatid stage. The number and size of Leydig cells were dramatically reduced. LuRKO females also displayed underdeveloped external genitalia and uteri postnatally, and their age of vaginal opening was delayed by 5-7 days. The (-/-) ovaries were smaller, and histological analysis revealed follicles up to the early antral stage, but no preovulatory follicles or corpora lutea. Reduced gonadal sex hormone production was found in each sex, as was also reflected by the suppressed accessory sex organ weights and elevated gonadotropin levels. Completion of meiosis of testicular germ cells in the LuRKO males differs from other hypogonadotropic/cryptorchid mouse models, suggesting a role for FSH in this process. In females, FSH appears to stimulate developing follicles from the preantral to early antral stage, and LH is the stimulus beyond this stage. Hence, in each sex, the intrauterine sex differentiation is independent of LH action, but it has a crucial role postnatally for attaining sexual maturity. The LuRKO mouse is a close phenocopy of recently characterized human patients with inactivating LHR mutations, although the lack of pseudohermaphroditism in LuRKO males suggests that the intrauterine sex differentiation in this species is not dependent on LH action.

Animals↗

Final heights in 45,X Turner's syndrome with spontaneous sexual development. Review of European and American reports.

STUDY OBJECTIVE: To assess the effect of endogenous estrogen secretion on the final heights of patients with 45,X Turner's syndrome. DESIGN: European and American reports of patients with 45,X Turner's syndrome and spontaneous sexual maturation in which final heights were available were analyzed and compared with existing norms for untreated patients with Turner's syndrome. Subgroups of patients were compared as a means of distinguishing low from normal endogenous estrogen exposure, and the effect of the age of menarche was assessed. PATIENTS: Twenty-three cases were collected, including eight who became pregnant. One had full somatic maturation but did not menstruate. RESULTS OF ANALYSES: Mean height of all 23 patients was 140.8 cm +/- 8.07 (s.d.) vs 143.1 cm +/- 6.0 (p = 0.035) for literature norms for Turner's syndrome. Mean height of those who achieved pregnancy was 138.6 cm +/- 8.21 (p = 0.035 vs literature norm); of those with normal gonadotropins 137.5 cm +/- 6.03; and of those with high gonadotropins 139.2 cm +/- 1.44 (p = 0.374). Age of menarche was available in 21 and showed no correlation with final height. CONCLUSIONS: Physiological and subphysiological endogenous secretion of estrogen in Turner's syndrome does not increase final height, suggesting that even low-dose exogenous estrogen would not increase ultimate stature in these patients.

Adolescent↗

Disruption of a Plasmodium falciparum gene linked to male sexual development causes early arrest in gametocytogenesis.

A male gametocyte defect in the Plasmodium falciparum Dd2 parasite was previously discovered through the observation that all progeny clones in a Dd2 x HB3 genetic cross were the result of fertilization events between Dd2 female and HB3 male gametes. A determinant linked to the defect in Dd2 was subsequently mapped to an 800-kb segment on chromosome 12. Here, we report further mapping of the determinant to an 82-kb region and the identification of a candidate gene, P. falciparum male development gene 1 (pfmdv-1), that is expressed at a lower level in Dd2 compared with the wild-type normal male gametocyte-producing ancestor W2. Pfmdv-1 protein is sexual-stage specific and is located on the gametocyte plasma membrane, parasitophorous vacuole membrane, and the membranes of cleft-like structures within the erythrocyte. Disruption of pfmdv-1 results in a dramatic reduction in mature gametocytes, especially functional male gametocytes, with the majority of sexually committed parasites developmentally arrested at stage I. The pfmdv-1-knockout parasites show disturbed membrane structures, particularly multimembrane vesicles/tubes that likely derive from deformed cleft-like structures. Mosquito infectivity of the knockout parasites was also greatly reduced but not completely lost. The results suggest that pfmdv-1 plays a key role in gametocyte membrane formation and integrity.

Animals↗

A chimeric homeodomain protein causes self-compatibility and constitutive sexual development in the mushroom Coprinus cinereus.

The A mating type genes of the mushroom Coprinus cinereus encode two classes of putative transcription factor with distinctive homeodomain motifs (HD1 and HD2). A successful mating brings together different allelic forms of these genes and this triggers part of a developmental sequence required for sexual reproduction. In this report we provide evidence that this developmental programme is promoted by a physical interaction between the two classes of homeodomain protein. Rare dominant mutations conferring self-compatibility map to the A locus and result in constitutive operation of the A-regulated developmental pathway. Our molecular analysis of one of these mutations shows that it has generated a chimeric gene by inframe fusion of an HD2 and an HD1 gene. Fusion has overcome the normal incompatibility between two proteins coded by genes of the same A locus and generated a protein that is sufficient to promote development in the absence of any other active A mating type genes. The fusion protein retains most of the HD2 sequence, but only the C-terminal part of the HD1 protein. It has only the HD2 homeodomain motif as a potential DNA binding domain fused to an essential C-terminal region of the HD1 protein, which in a normal HD1-HD2 protein complex may be the major activation domain.

Amino Acid Sequence↗

Testicular gamma-aminobutyric acid and circulating androgens in Syrian and Djungarian hamsters during sexual development.

Several factors, besides luteinizing hormone (LH), participate in the modulation of testicular function. A number of neurotransmitters are reported to be involved in this process, including a stimulatory action of gamma-aminobutyric acid (GABA) on steroidogenesis in the rat testis. The purpose of this study was to investigate the testicular pattern of GABA and glutamic acid, one of its main precursors, during sexual maturation in two seasonally breeding species: Syrian (golden) and Djungarian hamsters. Plasma androgen levels were also measured. The animals were maintained under long-day photoperiod (16:8, L:D) and were killed at 23, 30, 36, 46, 60, and 90 days of age. A different pattern of developmental changes in body and testicular weight was observed in these two species. GABA was present in the testes at all ages studied. GABA concentration and content showed a sharp elevation in the prepubertal period in golden as well as Djungarian hamsters. However, glutamic acid concentrations remained nearly constant during development in both species. Glutamic acid content increased gradually with age in the golden hamster, while a marked peak at 36 days of age was detected in the Djungarian hamster. Plasma testosterone and dihydrotestosterone levels were maximal at pubertal age in both species. The plasma levels of 5 alpha-androstane-3 alpha, 17 beta-diol increased significantly at 30 days of age in the golden hamster while in Djungarian hamsters this steroid remained unchanged. These results suggest that glutamic acid may serve as a precursor for GABA biosynthesis in the testis. In addition, changes in testicular GABA and plasma androgen levels might reflect a modulatory effect of this neurotransmitter in the acquisition of steroidogenic capability during development.

Androgens↗