Functions of filamin in brain development and diseases

细丝蛋白在大脑发育和疾病中的作用

• 批准号: 9281926
• 负责人: Yuanyi Feng
• 金额: $ 33.8万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9281926
• 关键词: Actin-Binding Protein; Adhesions; Affect; Anatomy; Apical; Bilateral; Blood Vessels; Brain; Brain Diseases; Bromodeoxyuridine; Cell Adhesion; Cell Polarity; Cell Therapy; Cells; Cerebral Ventricles; Cerebral cortex; Cerebrum; Clinic; Clinical; Cortical Malformation; Cytoskeleton; Data; Defect; Development; Developmental Process; Diagnosis; Disease; Dyslexia; Embryo; Epithelial; Etiology; Event; FLNA gene; Failure; Family member; Gene Expression Profile; Genes; Genetic; Goals; Human; Impairment; Intellectual functioning disability; Intercellular Junctions; Intractable Epilepsy; Kinetics; Knock-out; Lead; Link; Location; Mediating; Mesenchymal; Modeling; Molecular; Mus; Mutation; Neocortex; Neuroglia; Neurologic; Neuronal Migration Disorder; Neurons; Nodule; Partial Epilepsies; Pathogenesis; Pathologic; Patients; Pattern; Phenotype; Production; Protein Isoforms; Proteins; Radial; Radiology Specialty; Regulation; Research Proposals; Role; Series; Side; Signal Transduction; Stroke; Structure; Surface; System; Testing; Ventricular; brain cell; cell motility; cell type; feeding; filamin; gray matter; in vivo; insight; lateral ventricle; loss of function; loss of function mutation; migration; mouse model; mutant; nerve stem cell; neurodevelopment; neurogenesis; neuromechanism; neuropsychiatry; periventricular heterotopia; postnatal; progenitor; programs; public health relevance; subventricular zone; transcription factor; transcriptome sequencing

 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.

 描述(申请人提供)：脑室周围异位症(PH)是一种较常见的皮质发育畸形(MCD)，其特征是侧脑室周围灰质结节的异常存在和迟发性顽固性癫痫。编码肌动蛋白结合蛋白的X-连锁细丝蛋白A(FLNA)基因的突变被认为是导致PH的主要遗传原因。尽管在过去的三十年里，对细丝蛋白A进行了广泛的细胞分子研究，但Flna在大脑皮层神经发生和神经元迁移中的作用以及PH的发病机制仍然不清楚。这项提议提出了一套建立实验系统的方法，允许直接测试Flna在大脑皮层发育中的功能。为了达到这一目标，我们通过有条件地消除发育中皮质中的细丝素A(Flna)及其密切相关的家族成员细丝素B(FlNB)，建立了一种PH的小鼠模型。初步分析表明，这个小鼠模型概括了几乎所有由人类Flna突变引起的PH的解剖特征。我们使用这个PH模型的发育研究表明，FLNA在维持神经前体结构域的结构和组织以及神经元命运受限的中间神经前体(INPs)的神经源生态位方面发挥了以前未被认识到的作用。这一功能的丧失会导致INPs沿着脑室的错误定位和外来神经发生。这项提议的三个具体目标将验证这些发现，并通过1)进一步表征小鼠PH脑的解剖学特征，2)确定细丝素突变扰乱的发育过程，以及3)确定细丝素在大脑皮层正常和病理形成中的细胞分子功能，来进一步研究细丝蛋白调控的分子发育程序。这些目标的完成不仅将揭示PH的发病机制，还将为研究在发育中的大脑增强神经源性潜力的机制提供重要的见解。因此，这些研究的结果有望指导以神经干细胞为基础的治疗各种发育性大脑疾病的开发。