Hypothalamic-pituitary-gonadal axis in the mutant weaver mouse

The weaver (wv) mutant mouse manifests severe locomotor defects, a deficien cy in granule cells of the cerebellum, and cellular deficits in the midbrai n dopaminergic system. The wv phenotype is associated with a missense mutat ion 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 th ey 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 compariso n with wild-type controls. Testicular weight was significantly reduced in t he homozygous males, due to degenerative changes of seminiferous epithelium . Serum and pituitary content of luteinizing hormone (LH), follicle-stimula ting 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 con trol and mutant males showing higher GH than females. Serum testosterone le vels were normal in the mutants, as was testicular testosterone. Testicular alpha-inhibin content was mildly reduced, but high in proportion to testic ular weight. The defect in spermatogenesis appeared predominantly in the po stmeiotic stages. In situ hybridization was consistent with expression of s ome GIRK2 mRNA isoforms in seminiferous epithelium. There were no significa nt differences between genotypes in the levels of dopamine, dihydroxyphenyl acetic 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 monoamin e concentrations and normal sex differences in gonadotropins, we conclude t hat 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 sugge st that Leydig cell function, and at least some aspects of Sertoli cell fun ction, are normal in the mutant mice.