Outbred mouse stocks, often used in genetics, toxicology and pharmacology research, have been generated in rather haphazard ways. Understanding the characteristics of these stocks and their advantages and disadvantages is important for experimental design. In many studies these mice are used inappropriately, wasting animals' lives and resources on suboptimal experiments. Recently, however, researchers from the field of complex trait analysis have capitalized on the genetics of outbred stocks to refine the identification of quantitative trait loci. Here we assess the most widely used outbred stocks of mice and present guidelines for their use.

The hereditary ataxias are a complex group of neurological disorders characterized by the degeneration of the cerebellum and its associated connections. The molecular mechanisms that trigger the loss of Purkinje cells in this group of diseases remain incompletely understood. Here, we report a previously undescribed dominant mouse model of cerebellar ataxia, moonwalker (Mwk), that displays motor and coordination defects and loss of cerebellar Purkinje cells. Mwk mice harbor a gain-of-function mutation (T635A) in the Trpc3 gene encoding the nonselective transient receptor potential cation channel, type C3 (TRPC3), resulting in altered TRPC3 channel gating. TRPC3 is highly expressed in Purkinje cells during the phase of dendritogenesis. Interestingly, growth and differentiation of Purkinje cell dendritic arbors are profoundly impaired in Mwk mice. Our findings define a previously unknown role for TRPC3 in both dendritic development and survival of Purkinje cells, and provide a unique mechanism underlying cerebellar ataxia.cerebellum ͉ dendritogenesis ͉ trp channel ͉ mouse mutant T he inherited cerebellar ataxias are a complex group of neurodegenerative disorders characterized by loss of balance and coordination (1-3). Cerebellar ataxia is caused by the degeneration of Purkinje cells, which form the sole output of the cerebellum. To date, more than 50 different inherited forms of cerebellar ataxia are known (4). Importantly, increasing evidence points to the existence of common pathological pathways in different forms of ataxia, including transcriptional regulation, protein aggregation, and calcium homeostasis, which trigger the degeneration of Purkinje cells in these disorders (1, 5). However, the molecular mechanisms mediating these pathways remain poorly understood.To identify gene products that might be key to cerebellar degeneration, we used a phenotype-driven approach to screen for ataxic behavior in a large cohort of N-ethyl-N-nitrosourea (ENU)-mutagenized mice (6). Here, we report that a point mutation (T635A) in the C3-type transient receptor potential (TRPC3) channel in the mouse results in Purkinje cell degeneration and cerebellar ataxia. We also find that the development of dendrites is severely impaired in mutant Purkinje cells. Notably, the identified dominant gain-of-function mutation in TRPC3 provides insight into the function of TRPC3 that powerfully complements the findings obtained from the recently published TRPC3 knockout mouse (7). Our findings suggest that TRPC3 is a regulator of development and survival of Purkinje cells, and link aberrant TRPC3 function to cerebellar disease.

C201R, with a point mutation that leads to a non-conservative substitution within GARS. Heterozygous mice with a C3H genetic background have loss of grip strength, decreased motor flexibility and disruption of fine motor control; this relatively mild phenotype is more severe on a C57BL/6 background. Homozygous mutants have a highly deleterious set of features, including movement difficulties and death before weaning. Heterozygous animals have a reduction in axon diameter in peripheral nerves, slowing of nerve conduction and an alteration in the recovery cycle of myelinated axons, as well as innervation defects. An assessment of GARS levels showed increased protein in 15-day-old mice compared with controls; however, this increase was not observed in 3-month-old animals, indicating that GARS function may be more crucial in younger animals. We found that enzyme activity was not reduced detectably in heterozygotes at any age, but was diminished greatly in homozygous mice compared with controls; thus, homozygous animals may suffer from a partial loss of function. The Gars C201R mutation described here is a contribution to our understanding of the mechanism by which mutations in tRNA synthetases, which are fundamentally important, ubiquitously expressed enzymes, cause axonopathy in specific sets of neurons.

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