Pathological Mechanisms of Human Cerebellar Malformations

项目总结 虽然小脑在运动功能中的作用已经得到了很好的认识，但小脑在运动功能中也发挥着关键作用 情感调节、认知加工和语言功能(1)。事实上，越来越多的人认识到 小脑发育障碍会导致相当大的认知、行为和社交缺陷(2-6)。然而， 虽然小脑畸形是最常见的结构性脑畸形之一 产前检查(7-10)。关于其原因的可靠信息很少(11，12)。诊断的基础是 影像研究往往不可靠，这是一个在胎儿发育过程中放大的问题(13，14)。赤裸裸的 与几十年来关于驱动机制和基因的丰富知识形成对比 小鼠和其他模式生物的小脑发育(15-19)，我们实际上对人类知之甚少 小脑发育。我们最近报道了人类小脑发育的多个方面 与老鼠甚至猕猴不同，它是一种非人类的灵长类动物。这些发现挑战了我们目前的 以小鼠为中心的正常小脑发育模型及人类小脑发病机制 发育障碍(20例)。这项建议旨在提高对人类正常发育的认识。 小脑和小脑出生缺陷，利用我们接触正常和异常人类胎儿的独特途径 小脑组织和2)我们在小鼠和人类小脑发育方面的广泛、特定的专业知识和我们的 对人类小脑畸形有深入的了解。我们对正常和异常的详细描述 小脑发育，结合人源化的小鼠模型，将提高我们对 正常人类小脑发育的生物学和临床重要人类的发病机制 小脑出生缺陷，Dandy-Walker畸形(DWM)。它们将提供黄金标准的组织学和 转录数据集评估人类小脑发育的模型系统，生成第一个 “人性化”小鼠模型的人类小脑发育，最后，使改进和迫切需要 小脑畸形家系的产前诊断信息。

PROJECT SUMMARY While the cerebellum's role in motor function is well recognized, the cerebellum also plays cardinal roles in affective regulation, cognitive processing, and linguistic function (1). Indeed, there is a growing recognition that disruptions of cerebellar development cause considerable cognitive, behavioral, and social deficits (2-6). Yet, though cerebellar malformations are amongst the most commonly recognized structural brain malformation in prenatal imaging (7-10). Reliable information about their cause is sparse (11, 12). Diagnosis is based on imaging studies which are often unreliable, a problem amplified during fetal development (13, 14). In stark contrast to the wealth of knowledge gained over the decades regarding the mechanisms and genes driving cerebellar development in mice and other model organisms (15-19), we actually know very little about human cerebellar development. We recently reported multiple aspects of human cerebellar development significantly differing from mice and even rhesus macaque, a non-human primate. These discoveries challenge our current mouse-centric models of normal cerebellar development and the pathogenesis human cerebellar developmental disorders (20). This proposal seeks to advance knowledge of normal developing human cerebellum and cerebellar birth defects, leveraging 1) our unique access to normal and abnormal human fetal cerebellar tissue and 2) our extensive, specific expertise of mouse and human cerebellar development and our deep knowledge of human cerebellar malformations. Our detailed characterization of normal and abnormal cerebellar development, combined with humanized mouse models will improve our understanding of the biology of normal human cerebellar development and the pathogenesis of a clinically important human cerebellar birth defect, Dandy-Walker malformation (DWM). They will provide gold standard histological and transcriptomic datasets to assess model systems of human cerebellar development, generate the first “humanized” mouse models of human cerebellar development and finally, enable improved and sorely needed prenatal diagnostic information for families affected by cerebellar malformations.