Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
Eur J Neurosci. 2010 Sep;32(5):707-16. doi: 10.1111/j.1460-9568.2010.07330.x. Epub 2010 Aug 16.
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.
ROR-α 是一种孤儿核受体，其失活会导致小脑浦肯野细胞自主分化阻滞，并继发颗粒神经元丧失。作为我们ENU 诱变筛选的一部分，我们分离出隐性 tmgc26 突变鼠，其特征为早发性进行性共济失调、小脑变性和幼鼠致死。对 tmgc26/-小脑的详细分析显示浦肯野细胞和颗粒细胞异常，分子层中间神经元和放射状胶质缺陷。嵌合体研究表明 tmgc26 突变在浦肯野细胞和分子层中间神经元中具有自主效应，在颗粒细胞中具有非自主效应。该突变定位于 9 号染色体上的一个 13Mb 区间，该区间包含 ROR-α 基因。对基因组 DNA 的测序揭示了 ROR-α 基因外显子 5 中的 T 到 A 转换，导致无义突变 C257X 和 ROR-α 蛋白的严重截断。总之，我们的数据确定了 ROR-α 在分子层中间神经元和放射状胶质发育中的新作用，并提出 tmgc26 作为一种新的 ROR-α 等位基因，可用于进一步阐明 ROR-α 作用的分子机制。
