Phenotypic and genetic analysis of the cerebellar mutant tmgc26, a new ENU-induced ROR-alpha allele.
Phenotypic and genetic analysis of the cerebellar mutant tmgc26, a new ENU-induced ROR-alpha allele.
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DOI：
10.1111/j.1460-9568.2010.07330.x
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Chizhikov VV
中科院分区：
文献类型：
--
作者：
Swanson DJ;Steshina EY;Wakenight P;Aldinger KA;Goldowitz D;Millen KJ;Chizhikov VV
ROR-alpha is an orphan nuclear receptor, the 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 13Mb 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 introduce tmgc26 as a novel ROR-alpha allele suitable for further delineating molecular mechanisms of ROR-alpha action.
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