Identification of the weaver Mouse Mutation: The End of the Beginning

region of the GIRK2 protein. Identification of this mutation now provides a clear focus for determining the basis of the phenotypic sequelae that define the wv mouse. GIRK2 is part of a family of inwardly rectifying K ϩ Hershey, Pennsylvania 17033 channels that are activated by G protein subunits (Wick-man et al., 1994; Kofuji et al., 1995). These channels are Neurological mouse mutants have been studied for decades as models for neuronal development, pathogene-especially important in neuronal function, as they make a significant contribution to setting the resting potential sis, and neurologic disorders. Despite intensive research , very few of the mutant genes responsible for of the cell. Upon opening, these channels selectively permit K ϩ to enter the cell. With receptor mediated acti-the neurologic abnormalities in these mice have been identified. In fact, because the abnormal neurologic phe-vation, these channels influence the generation of slow synaptic potentials. GIRK channels are coupled to multi-notypes provide few clues to the underlying molecular defects, these mice generally bear names that are de-ple neurotransmitter receptors including opioid, adren-ergic, muscarinic, dopamine, and GABA B receptors (re-scriptors of their phenotypes, such as staggerer, star-gazer, tottering, lurcher, and shiverer. Many neurologi-viewed by Hille, 1992). Thus, a mutation in any one of these channels could affect signal transduction in sev-cal mouse mutants exhibit abnormalities of multiple cell types within the CNS at several developmental and adult eral neurotransmitter systems. Of the GIRK channels identified to date, GIRK1, stages adding greater complexity to the identification of the offending gene. That is, the effect of the mutation GIRK2, and GIRK3 are expressed in brain (Kofuji et al., 1996). GIRK2 is expressed only in brain and testis. In is pleiotropic where the single mutant gene is responsible for multiple effects on the phenotype. brain, there is considerable overlap in the distribution of the GIRK2 expression with GIRK1 and GIRK3 (Table The weaver (wv) mouse is one such mutant. The wv mutation results in the degeneration of neuronal popula-1), whereby GIRK1, GIRK2, and GIRK3 are all expressed in cerebellar granule cells and throughout the cortex tions as diverse as granule cells of the cerebellum and dopaminergic neurons in the substantia nigra, while (Kobayashi et al., 1995). In addition, GIRK2 is expressed in the hippocampus, substantia nigra, amygdala, pon-other cells of the CNS are spared. Surprisingly, it is a mutation resulting in the functional alteration of a potas-tine nuclei, olfactory bulb, and …