The robotic mouse is an autosomal dominant mutant that arose from a large-scale chemical mutagenesis program. It has a jerky, ataxic gait and develops adult-onset Purkinje cell loss in the cerebellum in a striking region-specific pattern, as well as cataracts. Genetic and physical mapping of the disease locus led to the identification of a missense mutation in a highly conserved region of Af4, a putative transcription factor that has been previously implicated in leukemogenesis. We demonstrate that Af4 is specifically expressed in Purkinje cells, and we hypothesize that the expression of mutant Af4 leads to neurodegeneration. This function was not identified through knock-out studies, highlighting the power of phenotype-driven mutagenesis in the mouse to identify new pathways involved in neurological disease.
10.1523/JNEUROSCI.23-05-01631.2003
Journal article
2003-03-01T00:00:00+00:00
23
1631 - 1637
6
Amino Acid Sequence, Animals, Antigens, CD, Cataract, Cell Count, Cerebellar Ataxia, Cerebellum, Conserved Sequence, DNA-Binding Proteins, Disease Models, Animal, Disease Progression, Flow Cytometry, Genes, Dominant, Mice, Mice, Neurologic Mutants, Molecular Sequence Data, Mutagenesis, Nuclear Proteins, Organ Specificity, Physical Chromosome Mapping, Point Mutation, Purkinje Cells, Sequence Homology, Amino Acid, Thymus Gland