Regulation of symmetric and asymmetric cell division during brain development

 描述（由申请人提供）：神经祖细胞在发育和成人大脑中保持自我更新和分化之间的平衡的严格控制，并且可以响应环境线索以开启更多的增殖或产生更多的分化细胞。这种自我平衡的控制不仅对正常发育很重要，而且对大脑的正常运作也至关重要。我们研究的长期目标是了解 如何自我更新和分化是在大脑发育过程中调节的，并将所获得的知识应用于开发更好的诊断工具和治疗发育性大脑疾病和脑癌的新治疗方法。本申请提出研究一种新的蛋白质相互作用网络，该网络对于控制神经祖细胞中的对称（自我更新）与不对称（分化）细胞分裂至关重要。在我们以前的研究中，我们已经证明，使用组合的细胞，胚胎学和遗传学的方法，G蛋白信号（RGS）介导的ephrin-B反向信号通路的调节器是必不可少的维持胚胎大脑皮层的神经祖细胞状态和Ga亚基信号通路是重要的激活神经元分化。我们已经确定了一个有丝分裂驱动蛋白，可以相互作用，并招募ephrin B/RGS蛋白进入分裂的神经前体细胞的中间体，表明肝配蛋白-B/RGS通路在神经前体细胞调节中的作用与细胞分裂的最后阶段胞质分裂有关。此外，我们最近鉴定了几种与活性Ga亚基相互作用的蛋白质，发现这些蛋白质与Gα亚基类似，可以激活神经发生。因此，我们建议进一步表征ephrin-B/RGS/有丝分裂驱动蛋白和Ga亚基相互作用网络的生化相互作用，并研究这些网络在塑造神经祖细胞决定对称或不对称分裂中的潜在功能。我们预计，从这项研究中获得的数据将最终有助于了解神经祖细胞中的分子相互作用是什么以及如何指导自我更新和分化之间的平衡，以及这些网络中的失调如何导致某些发育性脑疾病或肿瘤发生。

 DESCRIPTION (provided by applicant): Neural progenitor cells maintain a tight control of the balance between self-renewal and differentiation in the developing and adult brains and can respond to environmental cues to either switch on more proliferation or produce more differentiated cells. Such a homeostatic control is not only important for normal development but also critical for proper functioning of the brain. The long-term goal of our study is to understand how self- renewal and differentiation are regulated during brain development and to apply the obtained knowledge for developing better diagnostic tools and novel therapeutic approaches for treating developmental brain disorders and brain cancers. This application proposes to investigate a novel protein interaction network that is crucial for controlling symmetric (self-renewal) versus asymmetric (differentiation) cell division in neural progenitor cells. In our previous studies, we have demonstrated, using combined cellular, embryological, and genetic approaches, that the regulator of G protein signaling (RGS)-mediated ephrin-B reverse signaling pathway is essential for maintaining the neural progenitor cell state in the embryonic cerebral cortex and that the Ga subunit signaling pathway is important for activating neuronal differentiation. We have identified a mitotic kinesin that can interact with and recruit the ephrin B/RGS proteins into the midbody of dividing neural progenitor cells, suggesting that the role of the ephrin-B/RGS pathway in neural progenitor cell regulation is linked to cytokinesis, the final stage of cell division. In addition, we have recently identified several interacting proteins of th active Ga subunits and found that these proteins, similar to Gα subunit, could activate neurogenesis. We thus propose to further characterize the biochemical interaction of the ephrin-B/RGS/mitotic kinesin and Ga subunit interaction network and examine the potential function of these networks in shaping neural progenitor cells' decision to either divide symmetrically or asymmetrically. We anticipate that the data obtained from this study will ultimately help understand what and how molecular interactions in neural progenitor cells guides the balance between self-renewal and differentiation and how dysregulation in these networks may lead to certain developmental brain disorders or tumorigenesis.