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

描述（由申请人提供）：近年来，我们在理解大脑皮层是如何组装方面取得了巨大进步。叉头转录因子FoxG 1在皮质内广泛表达，但该基因的缺失导致如此严重的缺陷，以至于以前仅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FoxG 1在抑制早期皮质细胞类型（Cajal Retzius细胞）的命运中起作用，从而有利于主要锥体神经元的产生，从而大大有助于我们理解FoxG 1在发育中的作用（Hanashima et al.，2004; 2007）。不幸的是，即使有这样的努力，FoxG 1的广泛表达和早期的致命性与其功能的丧失，阻止了清楚地了解其在有丝分裂后皮质发育的作用。为了避免这种僵局，我们已经产生了两个增益的功能方法，以及一个有条件的FoxG 1功能等位基因的损失，这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，即下调FoxG 1作为锥体神经元进入多极相，然后上调，因为他们离开它所需的锥体命运规范和组装的皮质层。在这个建议中，我们试图了解FoxG 1如何介导这些关键的发育事件，探索FoxG 1水平的变化在不同的发展点是如何集中参与细胞和分子级联所需的适当的锥体神经元成熟。特别地，我们将关注1）FoxG 1在径向迁移和多极状态之间的选择中的作用2）在从早期多极向晚期多极过渡期间Netrin信号传导的负调节。 阶段和3）FoxG 1作为抑制下调基因，否则会干扰进入皮质板的要求。临床相关性：我们对许多受影响的精神障碍（如Rett综合征和精神发育迟滞）的遗传基础的理解受到了小鼠直接研究这些疾病的良好遗传模型的限制。在人类中，导致FoxG 1功能部分丧失的突变是病因学的基础。 这两种疾病。通过探索FoxG 1指导皮质和成人神经发生的遗传机制，我们的建议有可能最终为探索这些目前知之甚少的疾病的核心方面提供工具。

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.