细胞类型特定的替代拼接控制着发育中的大脑皮层中的细胞命运
Xiaochang Zhang1, Ming Hui Chen2, Xuebing Wu3
1Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Cell
|August 28, 2016
概括
在大脑发育过程中, 替代拼接动态地控制细胞命运. 关键蛋白质Ptbp1和Rbfox通过改变特定的基因外形来调节神经前代细胞的转变,从而影响神经元的分化,并可能导致大脑形.
科学领域:
- 神经科学
- 分子生物学
- 遗传学
背景情况:
- 替代拼接在哺乳动物的大脑中很普遍.
- 了解它在神经发育中的作用至关重要.
研究的目的:
- 研究替代拼接在神经原生细胞 (NPC) 分化中的功能作用.
- 在大脑皮层发育过程中确定替代拼接的关键调节器和目标.
主要方法:
- 来自哺乳动物大脑皮层的净化NPC和神经元的分析.
- 差异拼接外子及其蛋白质域变化的识别和特征.
- 研究Ptbp1和Rbfox蛋白在调节剪接中的对抗作用.
- 人类突变影响拼接及其与大脑形的关系的分析.
主要成果:
- 鉴定了数百个分别拼接的外基子,特别影响细胞骨蛋白质,并可能含有致病突变.
- 通过调节神经元特异性的前体,Ptbp1和Rbfox蛋白被证明对抗性地控制了NPC到神经元的过渡.
- Ptbp1通过抑制Flna的毒素前体来维持尖端前体,而Rbfox蛋白通过改变Ninein拼接来促进神经元分化.
- 在PTBP1结合部位发生的人体内基突变破坏了FLNA外基跳转,导致脑特异性形.
结论:
- 在大脑皮层发育过程中,替代拼接的动态控制对于细胞命运的确定至关重要.
- 如FLNA突变所示,拼接的失调会导致大脑形.
- Ptbp1和Rbfox是通过替代拼接进行神经前体细胞转变的关键对抗调节剂.
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