Spinal muscular atrophy genewobbler of the mouse: Evidence from chimeric spinal cord and testis for cell-autonomous function

Abstract

Human hereditary neurodegenerative diseases are genetically and mechanistically very heterogeneous and so are spinal muscular atrophies and cerebellar ataxias in the mouse, despite the common phenomenon of neuronal death. In this species, a number of mutations impair spermiogenesis in addition to neuron survival. Among these, the wobbler mutation on proximal chromosome 11 of the mouse leads to motoneuron degeneration in brain stem and spinal cord and to a defect of spermiogenesis. Chimeric mice of the type wr?/wr? → +/+ were produced, and their allelic status at the wr locus was determined by PCR diagnosis of a closely linked marker. Two overt chimeras, one female (XX → XX) and one male (XY → XY) were identified as wr/wr → +/+ and analyzed with respect to their pathological phenotype. Although there was patchy astrogliosis in the spinal cords of both chimeras, their motor performances were overtly normal and muscles were without signs of denervation. The male's testes revealed a mosaic pattern of normal and pathological spermatids. As no progeny was derived from wr spermatids, the spermatocytes 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. Dev Dyn 209:286–295, 1997. © 1997 Wiley‐Liss, Inc.

The wobbler mouse, an ALS animal model

“…The recessive inheritance indicates a loss-of-function effect and the investigation of chimeric mice pointed to a cell-autonomous effect of the wobbler mutation (Augustin et al 1997). …”

Homology between human Chromosome 2p13.3 and the wobbler critical region on mouse Chromosome 11: comparative high-resolution mapping of STS and EST loci on YAC/BAC contigs

“…For those ESTs the real position on the mouse STS/EST map cannot be revealed by PCR; hybridization techniques will be applied. Candidate genes by position should be expressed at least in testis and spinal cord (Augustin et al 1997) and therefore hybridizations on RNAs from the respective tissues will be performed to evaluate positional candidates by expression pattern.…”

“…In addition to a degeneration of motor neurons, the wobbler disease of the mouse comprises a defect in spermiogenesis. As shown by chimera experiments, these two cellular phenotypes seem to be autonomously expressed in the respective organs, spinal cord and testis, indicating the affected gene(s) must be expressed in those (Augustin et al 1997).…”

REVIEW ARTILCE: Cell therapy and stem cells in animal models of motor neuron disorders

“…In contrast to the SOD1 transgenic models of ALS, astrocyte and microglial activation has been reported to be initiated after motor neuron loss has begun (Rathke‐Hartlieb et al ., 1999). Consequently, a study using chimeras indicated that the effect of the wr gene (Vps54) is cell‐autonomous (Augustin et al ., 1997), although wobbler astrocytes have been shown to influence the survival of motor neurons (Ait‐Ikhlef et al ., 2000) and are probably contributing to motor neuron death in later stages of disease. The wobbler mouse has been widely used in growth factor delivery studies (Table 2).…”