Identification of the weaver mouse mutation: the end of the beginning.

The issue of why some cell types are more susceptible to the wv mutation remains a mystery. The cell death observed in wv mice is most easily explained by excitotoxicity. Neurons expressing wv GIRK2 are likely to have higher resting potentials than normal as a result of either unregulated Na+ influx via GIRK2 homomultimers or a reduction in K+ inward currents through heteromultimers. This chronic depolarization could ultimately result in toxicity and death. Further, reductions in internal K+ concentrations similar to that caused by wv GIRK2 induce death in immature granule neurons. The reduced K+ concentration results in the accumulation of excess Ca2+ through the mobilization of internal stores, which ultimately results in cell death (Levick et al. 1995xLevick, V, Coffey, H, and D'Mello, S.R. Brain Res. 1995; 676: 325–335Crossref | PubMed | Scopus (36)See all ReferencesLevick et al. 1995). Conversely, an increase in internal Ca2+ concentration in mature cultured granule neurons actually promotes cell survival, so developing granule cells appear to be especially vulnerable to high internal Ca2+ concentrations.Since most cell death in these mice occurs at developmental epochs in which large scale cell death is a normal phenomenon in both the cerebellum and substantia nigra, it is possible that abnormal K+ conductance coupled with excitotoxicity may potentiate cell death in an already vulnerable population. Cell death could also occur simply as a result of excessive metabolic demand. Some neuronal populations already under metabolic/oxidative stress may not be able to keep up with the additional stress of maintaining membrane potential in the face of unregulated Na+ influx. Dopaminergic cells are one such population under oxidative stress due to high rates of free radical production; with the additional stress of the wv mutation, these neurons may be especially vulnerable. Indeed, this is one mechanism of cell death proposed for Parkinson's disease.The most straightforward explanation for the selective cell death is that cells normally expressing high levels of GIRK2 are most vulnerable. This is supported by the differences in phenotype exhibited by heterozygous (+/wv) and homozygous (wv/wv) mice. The higher gene dosage in homozygotes clearly results in more profound cell death than the mild depletion observed in the heterozyogote, presumably due to the higher concentrations of mutant protein expressed; in this case, more is definitely not better.However, this simplistic explanation cannot completely account for the complex pattern of cell death observed in the cerebellum. Although granule cell and Purkinje cell loss in the wv/wv cerebellum is substantial, it is not total; the cell losses occur in a gradient with the most severe deficiencies occurring in the medial cerebellum while a population of more lateral cells are spared (Herrup and Trenkner 1987xHerrup, K and Trenkner, E. Neuroscience. 1987; 23: 871–885Crossref | PubMed | Scopus (72)See all ReferencesHerrup and Trenkner 1987). Since gradients of GIRK2 expression have been not observed in the cerebellum, it is unlikely that high concentrations of GIRK2 alone can account for the cell death. Instead, cell survival appears to be driven by environmental factors as well as genetic influences. Cell mixing experiments in which cerebellar precursors from wild-type and wv mice were combined result in the rescue of wv granule cells in vitro and in vivo (Gao et al. 1992xGao, W.-Q, Liu, X.-L, and Hatten, M.E. Cell. 1992; 68: 841–854Abstract | Full Text PDF | PubMed | Scopus (79)See all ReferencesGao et al. 1992), suggesting that in addition to the direct action of the mutant gene, cell–cell interactions clearly influence the survival of these cells.Like the granule and Purkinje neurons of the cerebellum, the death of the developing dopaminergic neurons is considerable but incomplete; marked reductions in tyrosine hydroxylase–positive neurons occur in the middle of the substantia nigra, whereas the dopaminergic cells situated more laterally are spared (Roffler-Tarlov et al. 1996xRoffler-Tarlov, S, Martin, B, Graybiel, A.M, and Kauer, J.S. J. Neurosci. 1996; 16: 1819–1826PubMedSee all ReferencesRoffler-Tarlov et al. 1996). As in the cerebellum, a gradient of cell death is observed. This gradient of dopaminergic cell death is not unique to the wv phenotype; similar patterns of dopaminergic cell death also occur in Parkinson's disease and MPTP intoxication, suggesting that there is inherent vulnerability in this cell group. Here again, neuronal susceptibility appears to be determined by both genetic and environmental influences. Clearly, electrophysiological experiments in conjunction with biochemical analyses will be essential for determining the precise mechanism(s) of cell death, a mechanism that may be unique for each cell type, consistent with the pleiotropic effects of the mutation.For over three decades, the mouse mutant wv has provided important basic information regarding the processes of neuronal development, migration, and death. Now, with the identification of the wv mutation, these studies also provide an exceptionally rich neuroscientific basis on which a sound understanding of the mechanisms leading from genotype to phenotype may be built. To paraphrase Churchill, this is not the beginning of the end, but the end of the beginning in the search for the mechanisms underlying the wv phenotype.