Regulation of symmetric and asymmetric cell division during brain development

 描述(申请人提供)：神经前体细胞在发育中和成年大脑中维持自我更新和分化之间的平衡，并能对环境信号做出反应，以开启更多的增殖或产生更多的分化细胞。这样的动态平衡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 如何在大脑发育过程中调节自我更新和分化，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。这项应用建议研究一种新的蛋白质相互作用网络，该网络对于控制神经前体细胞的对称(自我更新)和不对称(分化)细胞分裂至关重要。在我们以前的研究中，我们结合细胞、胚胎学和遗传学的方法，证明了G蛋白信号转导调节因子(RGS)介导的eaffin-B反向信号通路对于维持胚胎大脑皮层神经前体细胞的状态是必不可少的，而GA亚单位信号通路对于激活神经元分化是重要的。我们已经确定了一种有丝分裂激动素，它可以与ePhin相互作用并招募 B/RGS蛋白进入神经前体细胞分裂的中体，提示eaffin-B/RGS途径在神经前体细胞调控中的作用与胞质分裂有关，胞质分裂是细胞分裂的最后阶段。此外，我们最近还鉴定了几个TH活性GA亚基的相互作用蛋白，并发现这些蛋白类似于Gα亚基，可以激活神经发生。因此，我们建议进一步描述ePhrin-B/RGS/有丝分裂激动素和GA亚基相互作用网络的生化相互作用，并研究这些网络在决定神经前体细胞对称或不对称分裂方面的潜在功能。我们预计，从这项研究中获得的数据最终将有助于理解神经前体细胞中什么分子相互作用以及如何引导自我更新和分化之间的平衡，以及这些网络中的调节失调如何导致某些发育脑障碍或肿瘤发生。

 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.