Disruption of the nuclear hormone receptor ROR alpha in staggerer mice
Disruption of the nuclear hormone receptor ROR alpha in staggerer mice
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DOI：
10.1038/379736a0
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发表时间：
1996-02-22
期刊：
影响因子：
64.8
通讯作者：
Lander, ES
中科院分区：
文献类型：
--
作者：
Hamilton, BA;Frankel, WN;Lander, ES
由于浦肯野细胞发育中的细胞自主缺陷，HOMOZYGOUS staggerer（sg）小鼠表现出特征性的严重小脑共济失调（1，2）。这些细胞显示出不成熟的形态、突触排列、生化特性和基因表达，并且数量减少（3-12）。此外，sg杂合子表现出加速的树突萎缩和细胞丢失（13），表明sg在成熟的浦肯野细胞中起作用。这种突变对小脑发育的影响已经研究了25年，但其分子基础仍然未知，我们已经将staggerer遗传定位到小鼠9号染色体上的160个酶的间隔，发现其含有编码ROR α的基因，ROR α是核受体超家族的成员。发现Staggerer小鼠在ROR α基因内携带缺失，其阻止配体结合同源结构域的翻译。我们提出了一个基于这些结果的模型，其中ROR α与甲状腺激素信号通路相互作用，诱导浦肯野细胞成熟。
HOMOZYGOUS staggerer (sg) mice show a characteristic severe cerebellar ataxia due to a cell-autonomous defect in the development of Purkinje cells(1,2). These cells show immature morphology, synaptic arrangement, biochemical properties and gene expression, and are reduced in numbers(3-12). In addition, sg heterozygotes show accelerated dendritic atrophy and cell loss(13), suggesting that sg has a role in mature Purkinje cells. Effects of this mutation on cerebellar development have been studied for 25 years, but its molecular basis has remained unknown, We have genetically mapped staggerer to an interval of 160 kilobases on mouse chromosome 9 which was found to contain the gene encoding ROR alpha, a member of the nuclear hormone-receptor superfamily. Staggerer mice were found to carry a deletion within the ROR alpha gene that prevents translation of the ligand-binding homology domain. We propose a model based on these results, in which ROR alpha interacts with the thyroid hormone signalling pathway to induce Purkinje-cell maturation.