微头症基因将三胸和REST/NRSF联系起来,以控制神经干细胞的增殖和分化
Yawei J Yang1, Andrew E Baltus, Rebecca S Mathew
1Division of Genetics and Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
Cell
|November 27, 2012
概括
一个新发现的基因,ZNF335,通过破坏神经前体自我更新和神经发生,导致严重的小头. 这种指蛋白对大脑发育至关重要,它连接关键的基因调节通路.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 发育生物学 发展生物学
背景情况:
- 微头症是一种神经发育障碍,其特点是大脑皮层大小显著减少.
- 许多与小头症相关的基因会影响中枢细胞功能,影响细胞命运和增殖.
- 严重的小头症的遗传基础仍然不完全理解.
研究的目的:
- 识别和描述导致严重小头症的新型遗传因素.
- 阐明ZNF335调节大脑发育的分子机制.
- 确定ZNF335在人类神经发生和神经元分化中的作用.
主要方法:
- 对ZNF335基因的识别和表征.
- 产生和分析Znf335淘汰和条件淘汰小鼠模型.
- 在人体细胞中进行RNA干扰研究和对死后脑组织的分析.
- 研究ZNF335在三体H3K4-甲基化复合体中的作用及其对REST/NRSF的调节.
主要成果:
- 核指蛋白ZNF335被确定为严重的小头症,小体型和新生儿死亡率的致病基因.
- Znf335无菌小鼠表现出胚胎致死性,而条件淘汰会导致皮质大小严重减少.
- 正如RNAi和人类研究所证明的那样,ZNF335对于神经前体自我更新,神经发生和神经元分化至关重要.
- ZNF335作为脊椎动物特有的H3K4-甲基化复合物的组成部分,直接调节REST/NRSF和其他神经基因.
结论:
- ZNF335是人类神经发生和神经元分化的关键调节者.
- 这项研究提供了第一个直接的遗传证据,将ZNF335-H3K4-甲基化-REST/NRSF途径与人类大脑发育联系起来.
- ZNF335功能的失调代表了严重小头症背后的一个新机制.
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