The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and citron kinase
The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and citron kinase
复制标题
DOI：
10.1242/jcs.000703
复制
发表时间：
2007-06-01
影响因子：
4
通讯作者：
Di Cunto, Ferdinando
中科院分区：
文献类型：
--
作者：
Berto, Gaia;Camera, Paola;Di Cunto, Ferdinando
21号染色体上的唐氏综合征关键区（DSCR）包含许多基因，这些基因的重复可能导致唐氏综合征的主要表型特征，特别是相关的精神发育迟滞。然而，DSCR基因的功能大多是未知的，它们可能参与关键的大脑发育事件仍然在很大程度上未被探索。在这份报告中，我们表明，蛋白TTC 3，编码的主要DSCR候选基因之一，物理相互作用与柠檬酸激酶（CIT-K）和柠檬酸N（CIT-N），两个效应的RhoA小GTdR，以前参与神经元的增殖和分化。更重要的是，我们发现TTC 3水平可以通过CITK依赖性机制强烈影响NGF诱导的PC 12细胞分化。事实上，TTC 3过表达导致神经突延伸的强烈抑制，这可以通过CIT-K RNAi逆转。相反，TTC 3敲低刺激相同细胞中的神经突延伸。最后，我们发现，Rho，而不是Rho激酶，是必需的TTC 3分化抑制活性。我们的研究结果表明，TTC 3-RhoA-CIT-K通路可能是体内神经元发育的关键决定因素，其过度活跃可能会对正常分化程序产生不利影响。
The Down syndrome critical region (DSCR) on Chromosome 21 contains many genes whose duplication may lead to the major phenotypic features of Down syndrome and especially the associated mental retardation. However, the functions of DSCR genes are mostly unknown and their possible involvement in key brain developmental events still largely unexplored. In this report we show that the protein TTC3, encoded by one of the main DSCR candidate genes, physically interacts with Citron kinase (CIT-K) and Citron N (CIT-N), two effectors of the RhoA small GTPase that have previously been involved in neuronal proliferation and differentiation. More importantly, we found that TTC3 levels can strongly affect the NGF-induced differentiation of PC12 cells, by a CITK-dependent mechanism. Indeed, TTC3 overexpression leads to strong inhibition of neurite extension, which can be reverted by CIT-K RNAi. Conversely, TTC3 knockdown stimulates neurite extension in the same cells. Finally, we find that Rho, but not Rho kinase, is required for TTC3 differentiation-inhibiting activity. Our results suggest that the TTC3-RhoA-CIT-K pathway could be a crucial determinant of in vivo neuronal development, whose hyperactivity may result in detrimental effects on the normal differentiation program.