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The synaptic scaffolding protein CNKSR2 interacts with CYTH2 to mediate hippocampal granule cell development.
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2021-11-17 , DOI: 10.1016/j.jbc.2021.101427
Hidenori Ito 1 , Rika Morishita 1 , Mariko Noda 1 , Tomoki Ishiguro 1 , Masashi Nishikawa 1 , Koh-Ichi Nagata 2
Affiliation  

CNKSR2 is a synaptic scaffolding molecule that is encoded by the CNKSR2 gene located on the X chromosome. Heterozygous mutations to CNKSR2 in humans are associated with intellectual disability and epileptic seizures, yet the cellular and molecular roles for CNKSR2 in nervous system development and disease remain poorly characterized. Here, we identify a molecular complex comprising CNKSR2 and the guanine nucleotide exchange factor (GEF) for ARF small GTPases, CYTH2, that is necessary for the proper development of granule neurons in the mouse hippocampus. Notably, we show that CYTH2 binding prevents proteasomal degradation of CNKSR2. Furthermore, to explore the functional significance of coexpression of CNKSR2 and CYTH2 in the soma of granule cells within the hippocampal dentate gyrus, we transduced mouse granule cell precursors in vivo with small hairpin RNAs (shRNAs) to silence CNKSR2 or CYTH2 expression. We found that such manipulations resulted in the abnormal localization of transduced cells at the boundary between the granule cell layer and the hilus. In both cases, CNKSR2-knockdown and CYTH2-knockdown cells exhibited characteristics of immature granule cells, consistent with their putative roles in neuron differentiation. Taken together, our results demonstrate that CNKSR2 and its molecular interaction partner CYTH2 are necessary for the proper development of dentate granule cells within the hippocampus through a mechanism that involves the stabilization of a complex comprising these proteins.

中文翻译:

突触支架蛋白 CNKSR2 与 CYTH2 相互作用以介导海马颗粒细胞的发育。

CNKSR2 是一种突触支架分子,由位于 X 染色体上的 CNKSR2 基因编码。人类 CNKSR2 的杂合突变与智力障碍和癫痫发作有关,但 CNKSR2 在神经系统发育和疾病中的细胞和分子作用仍然缺乏特征。在这里,我们确定了一种分子复合物,包括 CNKSR2 和 ARF 小 GTP 酶 CYTH2 的鸟嘌呤核苷酸交换因子 (GEF),这是小鼠海马中颗粒神经元正常发育所必需的。值得注意的是,我们表明 CYTH2 结合可防止 CNKSR2 的蛋白酶体降解。此外,为了探讨 CNKSR2 和 CYTH2 共表达在海马齿状回颗粒细胞胞体中的功能意义,我们在体内用小发夹 RNA (shRNA) 转导小鼠颗粒细胞前体以沉默 CNKSR2 或 CYTH2 的表达。我们发现这种操作导致转导细胞在颗粒细胞层和门之间的边界处异常定位。在这两种情况下,CNKSR2 敲低和 CYTH2 敲低细胞都表现出未成熟颗粒细胞的特征,这与它们在神经元分化中的推定作用一致。总之,我们的研究结果表明,CNKSR2 及其分子相互作用伙伴 CYTH2 通过涉及稳定包含这些蛋白质的复合物的机制,对于海马内齿状颗粒细胞的正常发育是必需的。我们发现这种操作导致转导细胞在颗粒细胞层和门之间的边界处异常定位。在这两种情况下,CNKSR2 敲低和 CYTH2 敲低细胞都表现出未成熟颗粒细胞的特征,这与它们在神经元分化中的推定作用一致。总之,我们的研究结果表明,CNKSR2 及其分子相互作用伙伴 CYTH2 通过涉及稳定包含这些蛋白质的复合物的机制,对于海马内齿状颗粒细胞的正常发育是必需的。我们发现这种操作导致转导细胞在颗粒细胞层和门之间的边界处异常定位。在这两种情况下,CNKSR2 敲低和 CYTH2 敲低细胞都表现出未成熟颗粒细胞的特征,这与它们在神经元分化中的推定作用一致。总之,我们的研究结果表明,CNKSR2 及其分子相互作用伙伴 CYTH2 通过涉及稳定包含这些蛋白质的复合物的机制,对于海马内齿状颗粒细胞的正常发育是必需的。与它们在神经元分化中的假定作用一致。总之,我们的研究结果表明,CNKSR2 及其分子相互作用伙伴 CYTH2 通过涉及稳定包含这些蛋白质的复合物的机制,对于海马内齿状颗粒细胞的正常发育是必需的。与它们在神经元分化中的假定作用一致。总之,我们的研究结果表明,CNKSR2 及其分子相互作用伙伴 CYTH2 通过涉及稳定包含这些蛋白质的复合物的机制,对于海马内齿状颗粒细胞的正常发育是必需的。
更新日期:2021-11-17
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