Regulation of neural progenitor functions underlying cortical growth & complexity

 描述（由申请人提供）：人类智力的一个显著决定因素是我们大脑皮层的巨大尺寸和复杂性。新皮质在胚胎发生期间形成，然后在胎儿发育期间当祖细胞分化以填充皮质板时扩展。脑生长和形态发生的缺陷导致许多神经发育障碍、神经精神疾病和智力残疾。因此，理解大脑正常和异常功能的关键一步在于确定驱动新皮层生长的机制。通过鉴定功能不同的神经祖细胞群体，最显著的是心室放射状胶质细胞（vRG）、中间祖细胞（IP）和基底/外放射状胶质细胞（bRG），已经朝着这一目标取得了进展。这类祖细胞在啮齿类动物和人类中都很常见。然而，最近的研究提出，在人类中看到的新皮层扩大和复杂性可能部分是由于bRG和IP细胞的发生大幅增加，而这在啮齿动物中是看不到的。关于这种人类特异性扩张背后的机制，人们知之甚少。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。Foxp 1和Foxp 4在人新皮质中表达，因为vRG细胞转化为bRG和IP细胞，并且改变小鼠中Foxp 1和Foxp 4的功能以表明它们分别在控制bRG和IP细胞的产生中起关键作用的方式改变皮质发育。在这个提议中，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类新皮质中的表达。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，以及大脑皮层的整体大小和结构。最后，在目标3中，我们将定义Foxp蛋白介导其对新皮层生长的贡献的基因组靶点。

 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.