FoxG1 in the Development of Cerebral Cortex and the Adult Neural Niche.

描述(申请人提供)：近年来，在我们对大脑皮层如何组装的理解上取得了长足的进步。叉头转录因子FoxG1在皮质中广泛表达，但该基因的缺失导致了如此严重的缺陷，以至于以前只探索了该基因的最早作用。在过去的五年里，我的实验室通过证明FoxG1在抑制早期皮质细胞类型(Cajal Retzius细胞)的命运、有利于主要锥体神经元的产生方面发挥了作用，从而为我们理解FoxG1在发育中的作用做出了很大贡献(Hanashima等人，2004；2007)。不幸的是，即使在这种努力下，FoxG1的广泛表达和与其功能丧失相关的早期致命性也阻碍了人们对其在有丝分裂后皮质发育中的作用的清楚了解。为了绕过这一僵局，我们产生了功能增益方法以及条件性FoxG1功能等位基因丢失，这使得我们能够在这两种情况下检查锥体神经元。我们的初步结果支持我们的假设，即随着锥体神经元进入多极阶段，FoxG1的下调以及离开时的上调都是锥体命运指定和皮质层组装所必需的。在这个提案中，我们试图通过探索不同发育阶段FoxG1水平的变化如何集中参与适当的锥体神经元成熟所需的细胞和分子级联来了解FoxG1是如何调节这些关键的发育事件的。我们将特别关注1)FoxG1在径向迁移和多极态之间选择的作用2)从早期多极向晚期多极过渡过程中Netrin信号的负调控 阶段和3)需要FoxG1作为抑制，以下调基因，否则将干扰进入皮质板。临床相关性：我们对影响精神障碍的众多原因的遗传基础的了解，如Rett综合征和智力低下，一直受到良好的小鼠遗传模型的限制，无法直接研究这些疾病。在人类中，导致FoxG1部分功能丧失的突变是病因 这两种疾病。我们的建议是通过探索FoxG1指导皮质和成人神经发生的遗传机制，最终有可能为探索这些疾病的中心方面提供工具，这些方面目前知之甚少。

DESCRIPTION (provided by applicant): Great strides have been made in recent years in our understanding of how the cerebral cortex is assembled. The fork head transcription factor FoxG1 is widely expressed within the cortex but loss of this gene results in such severe deficits that only the earliest role of this gene has previously been explored. Over the past five years my laboratory has contributed considerably to our understanding of the role of FoxG1 in development by demonstrating that is plays a role in suppressing the fate of the early cortical cell type (the Cajal Retzius cell) in favor of the production of the principal pyramidal neurons (Hanashima et al., 2004; 2007). Unfortunately even with this effort, the widespread expression of FoxG1 and the early lethality associated with its loss of function has prevented clear understanding of its role in either postmitotic cortical development. To circumvent this impasse, we have generated both gain of function methods, as well as a conditional FoxG1 loss of function allele, which together allows us to examine pyramidal neurons in both these contexts. Our preliminary results support our hypothesis that both the downregulation of FoxG1 as pyramidal neurons enter the multipolar phase followed by upregulation as they leave it are required for pyramidal fate specification and assembly of cortical layers. In this proposal we seek to understand how FoxG1 mediates these critical developmental events by exploring how changes in FoxG1 levels at different points in development are centrally involved in the cellular and molecular cascades needed for proper pyramidal neuron maturation. In particular we will focus on 1) the role of FoxG1 in selecting between radial migration and the multipolar state 2) the negative regulation of Netrin-signaling during the transition from the early to late multipolar phase and 3) the requirement of FoxG1 as a repression to downregulate genes that otherwise would interfere with entry into the cortical plate. Clinical Relevance: Our understanding of the genetic basis for numerous causes of affected mental disorders, such as Rett syndrome and mental retardation, has been limited by good genetic models in mice to study these disorders directly. In humans mutations resulting in partial loss of function of FoxG1 underlies the etiology of both these disorders. Our proposal by exploring the genetic mechanisms by which FoxG1 directs both cortical and adult neurogenesis has the potential to ultimately provide tools for exploring central aspects of these disorders that are at present poorly understood.