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      Hypothalamic-Pituitary-Gonadal Axis in the Mutant Weaver Mouse

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          The weaver (wv) mutant mouse manifests severe locomotor defects, a deficiency in granule cells of the cerebellum, and cellular deficits in the midbrain dopaminergic system. The wv phenotype is associated with a missense mutation in the pore region of the G-protein-gated inwardly rectifying potassium channel, GIRK2. The homozygous male wv mouse is essentially infertile due to an inadequate level of sperm production. Females are fertile although they also manifest the neurological phenotype. Homozygotes of both sexes have reduced body weight. We have evaluated the hypothalamic-pituitary-gonadal axis in heterozygote and homozygote male and female wv mutants in comparison with wild-type controls. Testicular weight was significantly reduced in the homozygous males, due to degenerative changes of seminiferous epithelium. Serum and pituitary content of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin were normal in all groups, and the normal sex differences were noted (FSH and LH higher in males, prolactin higher in females). Pituitary growth hormone (GH) concentration was normal, with control and mutant males showing higher GH than females. Serum testosterone levels were normal in the mutants, as was testicular testosterone. Testicular α-inhibin content was mildly reduced, but high in proportion to testicular weight. The defect in spermatogenesis appeared predominantly in the postmeiotic stages. In situ hybridization was consistent with expression of some GIRK2 mRNA isoforms in seminiferous epithelium. There were no significant differences between genotypes in the levels of dopamine, dihydroxyphenylacetic acid, serotonin and 5-hydroxyindoleacetic acid in the mediobasal and preoptic hypothalamic regions. Homovanillic acid levels in these two areas were, however, reduced in wv homozygotes compared to wild-type animals. In the light of normal pituitary hormone levels, normal hypothalamic monoamine concentrations and normal sex differences in gonadotropins, we conclude that the infertility in the male homozygote wv mouse lies within the tubule and is probably a primary defect in the germ cells. The hormonal data suggest that Leydig cell function, and at least some aspects of Sertoli cell function, are normal in the mutant mice.

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          Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice.

          The inhibins are alpha:beta heterodimeric growth factors that are members of the transforming growth factor-beta family. To understand the physiological roles of the inhibins in mammalian development and reproduction, a targeted deletion of the alpha-inhibin gene was generated by homologous recombination in mouse embryonic stem cells. Mice homozygous for the null allele (inhibin-deficient) initially develop normally but every mouse ultimately develops mixed or incompletely differentiated gonadal stromal tumours either unilaterally or bilaterally. Inhibin is thus a critical negative regulator of gonadal stromal cell proliferation and the first secreted protein identified to have tumour-suppressor activity.
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            Patterning of the Drosophila embryo by a homeodomain-deleted Ftz polypeptide.

            Homeodomain proteins regulate diverse developmental processes in a wide range of organisms, yet bind in vitro to DNA sequences that are remarkably similar. This has raised the fundamental question of how target gene specificity is achieved in vivo. The Drosophila fushi tarazu protein (Ftz) contains a homeodomain and is required for the formation of alternate segments. We have shown previously that a homeodomain-deleted Ftz polypeptide (Ftz delta HD), incapable of binding DNA in vitro, could regulate endogenous ftz gene expression. Here we test Ftz delta HD activities in a ftz mutant background and find that, surprisingly, Ftz delta HD can directly regulate ftz-dependent segmentation, suggesting that it can control target gene expression through interactions with other proteins. A likely candidate is the pair-rule protein Paired (Prd). Ftz delta HD bound directly to Prd in vitro and required Prd to repress wingless in vivo. These results emphasize the pivotal importance of protein-protein interactions in homeodomain protein function.
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              Characterization of avian T-cell receptor γ genes


                Author and article information

                S. Karger AG
                December 1998
                18 December 1998
                : 68
                : 6
                : 374-385
                a Department of Neurobiology and Physiology, Northwestern University, Evanston, Ill., and Departments of b Pathology and Laboratory Medicine, and c Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Ind., d Department of Pharmacological and Physiological Sciences, University of Chicago, Ill., USA
                54387 Neuroendocrinology 1998;68:374–385
                © 1998 S. Karger AG, Basel

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                Page count
                Figures: 9, Tables: 1, References: 53, Pages: 12
                Gonadotropin-Releasing Hormone and Regulation of the Gonadal Axis


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