Phenotypic and genetic analysis of the cerebellar mutant tmgc26 , a new ENU‐induced ROR‐alpha allele

作者：Douglas J. Swanson, Ekaterina Y. Steshina, Paul Wakenight, Kimberly A. Aldinger, Dan Goldowitz, Kathleen J. Millen, Victor V. Chizhikov · 发表于：European Journal of Neuroscience · 年份：2010 · DOI：10.1111/j.1460-9568.2010.07330.x · 被引用次数：14 · 研究领域：Vestibular and auditory disorders、Neurogenesis and neuroplasticity mechanisms、Neuroscience and Neuropharmacology Research

ROR-alpha is an orphan nuclear receptor, inactivation of which cell-autonomously blocks differentiation of cerebellar Purkinje cells with a secondary loss of granule neurons. As part of our ENU mutagenesis screen we isolated the recessive tmgc26 mouse mutant, characterized by early-onset progressive ataxia, cerebellar degeneration and juvenile lethality. Detailed analysis of the tmgc26-/- cerebella revealed Purkinje cell and granule cell abnormalities, and defects in molecular layer interneurons and radial glia. Chimera studies suggested a cell-autonomous effect of the tmgc26 mutation in Purkinje cells and molecular layer interneurons, and a non-cell-autonomous effect in granule cells. The mutation was mapped to a 13-Mb interval on chromosome 9, a region that contains the ROR-alpha gene. Sequencing of genomic DNA revealed a T-to-A transition in exon 5 of the ROR-alpha gene, resulting in a nonsense mutation C257X and severe truncation of the ROR-alpha protein. Together, our data identify new roles for ROR-alpha in molecular layer interneurons and radial glia development and suggest tmgc26 as a novel ROR-alpha allele that may be used to further delineate the molecular mechanisms of ROR-alpha action.