Male‐sterile phenotype of the neurological mouse mutant weaver

Abstract

The autosomal recessive murine mutation weauer (wu) affects postnatal differentiation in at least three neuronal populations in the brain: dopamine-containing neurons in the midbrain, and granule and Purkinje cells in the cerebellum. Neuronal populations vulnerable to the actions of weaver die in the midst of development. In addition, homozygous weaver males are sterile. We show by a histological analysis of epididymides and testes that the cause of male sterility in weaver is lack of sperm. The epididymides of the adult weaver mice examined were devoid of sperm, and few seminiferous tubules in the adult weaver's testes contained elongated spermatids. Most tubules were marked by moderate to severe degeneration of the seminiferous epithelium. A developmental study showed that the mutant phenotype emerged after the third postnatal week. By postnatal day 28, the development of weaver sperm lagged behind that of the wild-type and some seminiferous tubules contained degenerating germ cells. By postnatal day 35, terminal differentiation of spermatids appeared to be arrested in many tubules and degeneration of the seminiferous epithelium was widespread. The heterozygotes were unaffected at all ages sampled. We conclude that the normal allele at the weaver locus is necessary for spermiogenesis and the maintenance of spermatogenesis. 0 1994 Wiley-Liss, Inc.

Sperm GIRK2-Containing K+Inward Rectifying Channels Participate in Sperm Capacitation and Fertilization

“…Genetic analyses have indicated that homozygous weaver (wv/wv) mutation is associated with loss of granule cells in the cerebellum and dopaminergic neurons in the midbrain. This mutation leads to loss of the G-protein-mediated inward rectifier K + ion currents, subsequently resulting in chronic depolarization and reduced selectively for K + ions over Na + and Ca ++ ions [Abraham et al 1999;Corey and Clapham 2001;Harrison and Roffler-Tarlov 1994;Navarro et al 1996;Surmeier et al 1996;Wei et al 1998]. Our studies have confirmed that GIRK inward-rectifying K + ion channel expression profiles in the seminiferous epithelium of the testis are drastically different from the brain.…”

“…Genetic and molecular analysis of an increasing number of transgenic mouse models with defects in spermatogenesis have supported the hypothesis that voltage activated ion channels play a significant role in male germ cell differentiation and sperm morphogenesis [Harada et al 2003;Harrison and Roffler-Tarlov 1994]. These genetic animal models have made significant contributions toward supporting the current dogma that regulation of intracellular ions is critical for mediating the morphological changes observed during mouse spermiogenesis [Harada et al 2003;Harrison and Roffler-Tarlov 1994]. The Girk2 null mice are fertile [Signorini et al 1997], possibly due to compensation by related Girk genes.…”

“…Electrophysiological studies suggested that altered sperm membrane potential due to defective K + transport was responsible for several cases of male infertility [Calzada and Tellez 1997]. Genetic and molecular analysis of an increasing number of transgenic mouse models with defects in spermatogenesis have supported the hypothesis that voltage activated ion channels play a significant role in male germ cell differentiation and sperm morphogenesis [Harada et al 2003;Harrison and Roffler-Tarlov 1994]. These genetic animal models have made significant contributions toward supporting the current dogma that regulation of intracellular ions is critical for mediating the morphological changes observed during mouse spermiogenesis [Harada et al 2003;Harrison and Roffler-Tarlov 1994].…”

“…Previous Girk2 expression studies of weaver homozygous mice utilized histological analysis on sections of the seminiferous epithelium [Harrison and Roffler-Tarlov 1994;Vogelweid, et al 1993]. These investigators reported that spermatid development was impaired in the weaver testis and thus responsible for the male infertility phenotype observed in these animals.…”

“…The Girk2 null mice are fertile [Signorini et al 1997], possibly due to compensation by related Girk genes. However, extensive genetic and molecular studies of the male-infertile 'weaver' transgenic mice, carrying a gain of function mutation in Girk2 gene, suggest that the GIRK2 inward-rectifying K + ion channel plays a functional role in sperm development [Felix et al 2002;Harrison and Roffler-Tarlov 1994;Vogelweid et al 1993]. The exact molecular mechanisms involved in mediating male germ cell dysfunction are currently unknown.…”