Congenital brain malformations caused by aberrant head mesenchymal signaling

描述（由申请人提供）：本申请描述了一种跨学科的方法，包括基础和临床科学家采用新的和创新的信息学，遗传学和发育策略来确定Dandy-Walker畸形的潜在发病机制和致病基因，Dandy-Walker畸形是小脑最常见的结构畸形。Dandy-Walker畸形很常见，影响1/3000的活产婴儿，并导致严重的运动和智力迟缓，但人们对其知之甚少。我们的小组已经确定了这种临床和遗传异质性出生缺陷的仅有的2个特征位点。我们对小鼠模型的分析使我们得出这样的假设：对发育中的小脑的间充质信号的破坏对这种出生缺陷的发育发病机制至关重要。认识到脑膜是中枢神经系统发育的关键调节器是神经发育领域最近的一个范式转变，这些相互作用的基本生物学和分子途径尚不清楚。此外，很明显，脑膜信号的破坏不仅是后窝疾病（如Dandy-Walker）的重要临床表型的基础，而且对包括ACC等在内的大量涉及脑膜信号的神经发育障碍的发病机制具有广泛的影响。本实验旨在以最近发现的ddy - walker基因Foxc1为切入点，确定后颅窝间充质调节小脑发育的途径和机制。目的1-3采用新颖的体外和体内试验，包括外植体培养、电穿孔、RNAi和BAC转基因，以及广泛的信息分析，以确定和验证从后窝到邻近发育中的小脑的信号通路，这些信号通路调节小鼠模型中的ddy - walker相关表型。在Aim 4中，我们将在人类Dandy-Walker患者队列中对前3个目标中最佳的Dandy-Walker候选者进行测序，以确定新的致病基因。这些小鼠和人类的协同实验将定义神经发育间质控制的新生物学，并确定新的DWM基因，这将立即提高对受影响家庭的诊断，并将对未来的预后研究至关重要。

DESCRIPTION (provided by applicant): This application describes an interdisciplinary approach involving basic and clinical scientists employing new and innovative informatic, genetic and developmental strategies to identify the underlying pathogenesis and causative genes for Dandy-Walker malformation, the most common structural malformation of the cerebellum. Dandy-Walker malformation is common, affecting 1/3000 live births and causes significant motor and intellectual delay and yet is poorly understood. Our group has identified the only 2 characterized loci for this clinically and genetically heterogeneous birth defect. Our analysis of mouse models has lead us to the hypothesis that disruption of mesenchymal signaling to the developing cerebellum is critical to the developmental pathogenesis of this birth defect. The recognition that the meninges is a critical regulator of CNS development is a recent paradigm shift in the field of neurodevelopment and the basic biology and molecular pathways of these interactions is not known. Further, it has become apparent that disrupted meningeal signaling underlies not only the significant clinical phenotypes of posterior fossa disorders such as Dandy-Walker, but has broad implications for the pathogenesis of large group of neurodevelopmental disorders that also involve meningeal signaling including ACC and others. The experiments outlined in this proposal are designed to identify pathways and mechanisms for posterior fossa mesenchymal regulation of cerebellar development, using Foxc1, the most recently identified Dandy-Walker gene, as an entry point. Aims 1-3 use novel in vitro and in vivo assays including explant culture, electroporation, RNAi and BAC transgenesis together with extensive informatic analyses to identify and validate the signaling pathways from the posterior fossa to the adjacent developing cerebellum which modulate Dandy-Walker related phenotypes in mouse models. In Aim 4 we will then sequence the best Dandy-Walker candidates from the first 3 Aims, in a cohort of human Dandy-Walker patients to identify new disease-causative genes. Together these synergistic mouse and human experiments will define new biology regarding mesenchymal control of neural development and identify new DWM genes, which will immediately improve diagnosis for affected families and will be essential for future prognostic studies.