Functions of filamin in brain development and diseases

 描述（由申请人提供）：脑室周围异位（PH）是一种相对常见的皮质发育畸形（MCD），其特征为沿侧脑室沿着出现灰质结节和迟发性难治性癫痫。在X-连锁细丝蛋白A（FLNA）基因，编码肌动蛋白结合蛋白的突变，被认为是PH的主要遗传原因。尽管广泛的细胞分子研究细丝蛋白A在过去的三十年中，FLNA的作用，在大脑皮层神经发生和神经元迁移的发展机制，以及PH的发病机制，仍然难以捉摸。该建议提出了一套方法来建立一个实验系统，让FLNA的功能在大脑皮层发育直接测试。为了实现这一目标，我们通过有条件地消除发育中的皮质中的细丝蛋白A（Flna）及其密切相关的家族成员细丝蛋白B（Flnb）来产生PH的小鼠模型。初步分析表明，该小鼠模型几乎概括了人类FLNA突变引起的PH的所有解剖特征。我们的发展研究，使用这种PH模型表明，以前未被认识到的FLNA在维持神经祖细胞结构和组织的结构和神经元的命运限制的中间神经祖细胞（INPs）的神经原生态位。这种功能的丧失导致INPs沿着脑室的错误定位和外源性神经发生。本提案的三个具体目标将验证这些发现，并通过以下方式进一步研究细丝蛋白控制的分子发育程序：1）进一步表征小鼠PH脑的解剖学特征，2）确定细丝蛋白突变破坏的发育过程，3）鉴定细丝蛋白在大脑皮层正常和病理形成中的细胞分子功能。这些目标的完成不仅将揭示PH的发病机制，而且还提供了重要的见解，通过这些机制，神经原性潜力可能会在发育中的大脑中得到增强。因此，这些研究的结果有望指导基于神经干细胞的治疗方法的发展，用于各种各样的发育性脑疾病。

 DESCRIPTION (provided by applicant): Periventricular heterotopia (PH) is one of the relatively common malformations of cortical development (MCD) characterized by the abnormal presence of gray matter nodules along the lateral ventricle and late-onset intractable epilepsy. Mutations in the X-linked filamin A (FLNA) gene, which encodes an actin binding protein, are known to be the leading genetic cause of PH. Despite extensive cell molecular studies of filamin A in the past three decades, the developmental mechanism underlying FLNA's role in cerebral cortical neurogenesis and neuronal migration, as well as the pathogenesis of PH, remains elusive. This proposal presents a set of approaches to establish an experimental system to allow FLNA's function in cerebral cortical development to be tested directly. Towards this goal, we generated a mouse model of PH by conditionally eliminating filamin A (Flna) in the developing cortex together with its closely related family member filamin B (Flnb). Preliminary analyses showed that this mouse model recapitulated almost all anatomical features of PH caused by human FLNA mutations. Our developmental studies using this PH model suggested a previously unrecognized role of FLNA in maintaining the structure and organization of neural progenitor domains and the neurogenic niche of neuronal fate restricted intermediate neural progenitors (INPs). Loss of this function leads the mislocalization and extraneous neurogenesis of INPs along the brain ventricles. The three specific aims of this proposal will validate these findings and further investigate the molecular developmental programs governed by filamin by 1) further characterizing anatomical features of the mouse PH brain, 2) determining the developmental processes disrupted by filamin mutations, and 3) identifying the cell molecular functions of filamin in normal and pathological formation of the cerebral cortex. The completion of these aims will not only reveal the pathogenesis of PH, but also provide important insights into mechanisms through which the neurogenic potential may be enhanced in the developing brain. Results from these studies are thus expected to guide the development of neural stem cell based therapies for a wide variety of developmental brain disorders.