Regulation of neural progenitor functions underlying cortical growth & complexity

 描述(由申请人提供)：人类智力的一个显着决定因素是我们的大脑皮层的巨大尺寸和复杂性。新皮质在胚胎发育期间形成，然后在胚胎发育期间扩大，当祖细胞分化到皮质板上时。大脑生长和形态发生的缺陷会导致一系列神经发育障碍、神经精神疾病和智力残疾。因此，了解大脑的正常和异常功能的关键一步在于确定驱动新皮质生长的机制。通过鉴定功能不同的神经前体细胞群，最突出的是脑室径向神经胶质细胞(VRG)、中间神经前体细胞(IP)和基底/外径向神经胶质细胞(BRG)，朝着这一目标取得了进展。这类祖细胞在啮齿动物和人类中都是常见的。然而，最近的研究表明，在人类中看到的新皮质的扩大和复杂性可能部分是由于BRG和IP细胞的起源大幅增加，而啮齿动物中没有这种细胞。令人惊讶的是，人们对这种人类特有的扩张背后的机制知之甚少。我们的初步实验表明，FoxP转录因子是这一过程的重要组成部分。Foxp1和Foxp4在VRG细胞转化为BRG和IP细胞的过程中在人的新皮质中表达，而Foxp1和Foxp4功能的改变改变了小鼠的皮质发育，表明它们分别在控制BRG和IP细胞的产生方面发挥着关键作用。在这项提案中，我们将确定FoxP蛋白在小鼠和人类皮质发育中的功能。在目标1中，我们将表征FoxP蛋白在发育中的小鼠和人的新皮质中的表达。在目标2中，我们将确定FoxP功能的操纵如何改变BRG和IP细胞的产生，以及大脑皮层的总体大小和结构。最后，在目标3中，我们将定义FoxP蛋白的基因组靶点，这些靶点介导它们对新皮质生长的贡献。

 DESCRIPTION (provided by applicant): A notable determinant of human intellectual capacity is the enormous size and complexity of our neocortex. The neocortex forms during embryogenesis and then expands during fetal development when progenitors differentiate to populate the cortical plate. Defects in brain growth and morphogenesis result in a host of neurodevelopmental disorders, neuropsychiatric diseases, and intellectual disabilities. A key step towards understanding the normal and abnormal functions of the brain thus lies in defining the mechanisms driving neocortical growth. Progress towards this goal has been made though the identification of functionally distinct neural progenitor populations, most prominently ventricular radial glia (vRG), intermediate progenitor (IP), and basal/outer radial glia (bRG) cell. These classes of progenitors are common to both rodents and humans. However, recent studies have proposed that the neocortical enlargement and complexity seen in humans may result in part from a substantial increase in the genesis of bRG and IP cells that is not seen in rodents. Remarkably little is known about the mechanisms behind this human-specific expansion. Our preliminary experiments implicate Foxp transcription factors as important components to this process. Foxp1 and Foxp4 are expressed in the human neocortex as vRG cells transform into bRG and IP cells, and altering Foxp1 and Foxp4 functions in mouse changes cortical development in a manner suggesting that they play pivotal roles controlling the production of bRG and IP cells respectively. In this proposal, we will determine the function of Foxp proteins in both mouse and human cortical development. In Aim 1 we will characterize the expression of Foxp proteins in the developing mouse and human neocortex. In Aim 2, we will determine how manipulation of Foxp functions alters the generation of bRG and IP cells, and the overall size and structure of the cerebral cortex. Lastly, in Aim 3 we will define the genomic targets of Foxp proteins mediating their contributions to neocortical growth.