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

描述（由申请人提供）：近年来，我们对大脑皮层如何组装的理解取得了重大进展。叉头转录因子FoxG1在皮层中广泛表达，但该基因的缺失导致了严重的缺陷，因此之前只探索了该基因的早期作用。在过去的五年中，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）的命运有利于主要金字塔神经元的产生方面发挥作用，对我们对FoxG1在发育中的作用的理解做出了重大贡献（Hanashima et al., 2004; 2007）。不幸的是，即使有这样的努力，FoxG1的广泛表达和与功能丧失相关的早期致命性阻碍了对其在有丝分裂后皮层发育中的作用的清晰理解。为了避免这一僵局，我们生成了功能增益方法，以及条件FoxG1功能缺失等位基因，这两种方法使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FoxG1在锥体神经元进入多极期时下调，然后在它们离开多极期时上调，这是锥体命运规范和皮质层组装所必需的。在本研究中，我们试图通过探索FoxG1水平在发育不同阶段的变化如何集中参与锥体神经元成熟所需的细胞和分子级联反应，来了解FoxG1如何介导这些关键的发育事件。我们将特别关注1)FoxG1在径向迁移和多极状态之间的选择中的作用2)从多极早期到晚期过渡期间netrin信号的负调控

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.