SPINAL MUSCULAR-ATROPHY GENE WOBBLER OF THE MOUSE - EVIDENCE FROM CHIMERIC SPINAL-CORD AND TESTIS FOR CELL-AUTONOMOUS FUNCTION

Human hereditary neurodegenerative diseases are genetically and mechan istically very heterogeneous and so are spinal muscular atrophies and cerebellar ataxias in the mouse, despite the common phenomenon of neur onal death. In this species, a number of mutations impair spermiogenes is in addition to neuron survival. Among these, the wobbler mutation o n proximal chromosome 11 of the mouse leads to motoneuron degeneration in brain stem and spinal cord and to a defect of spermiogenesis. Chim eric mice of the type wr?/wr? - +/+ were produced, and their allelic s tatus at the wr locus was determined by PCR diagnosis of a closely Lin ked marker. Two overt chimeras, one female (XX <----> XX) and one male (XY <----> XY) were identified as wr/wr H +/+ and analyzed with respe ct to their pathological phenotype. Although there was patchy astrogli osis in the spinal cords of both chimeras, their motor performances we re overtly normal and muscles were without signs of denervation. The m ale's testes revealed a mosaic pattern of normal and pathological sper matids. As no progeny was derived from wr spermatids, the spermatocyte s appear as a primary target of the wr mutation in testis. Our results argue against a humoral mechanism of the wobbler disease and indicate a cell-autonomous action of the wr gene both in testis and in spinal cord. (C) 1997 Wiley-Liss, Inc.