Pathological Mechanisms of Human Cerebeller Malformations

项目摘要/摘要 在人类中已经描述了大量的小脑畸形。大多数原因是认知，除了 运动和感觉统合缺陷。令人惊讶的是，人们对儿童的发育基础知之甚少。 这些畸形，特别是因为几乎没有关于正常或异常胎儿的人类特有数据 小脑发育。这项建议旨在促进对人类小脑发育和 使用人类胎儿样本和小鼠模型的畸形。人类特有的数据将直接测试 关于这些疾病的原因，我们工作的小鼠衍生的假设的有效性，并加强了 正常发育数据的基础，这将为我们正在进行的人类小脑遗传分析提供信息 畸形。我们将首次对正常人类胎儿小脑发育进行深入分析 妊娠4-23周，涵盖重大发育事件。然后我们将研究人类的病理学 胎儿Dandy-Walker畸形--人类最常见的小脑畸形，约1/3000人存活 出生。将结合这些实验产生小鼠模型，以评估 发育病理学。最后，我们将生成第一个正常人类胎儿的转录组数据 小脑神经元。这些细胞类型的特定数据在目前公开的大脑中严重缺失 资源。我们的人类胎儿小脑神经元数据将与现有的转录组数据进行比较 内源性小鼠发育小脑神经元以及MES和hPSC来源小脑的数据集 神经元的发展，以评估其作为模型系统的有效性。此外，数据还将与 来自人类小脑畸形患者的外显子组数据，以促进这些重要和 未被充分研究的出生缺陷。

PROJECT SUMMARY/ABSTRACT Numerous cerebellar malformations have been described in humans. Most cause cognitive, in addition to motor and sensory integration deficits. Surprisingly little is understood regarding the developmental basis of these malformations, particularly since little human specific data is available for normal or abnormal fetal cerebellar development. This proposal seeks to advance knowledge of human cerebellar development and malformations using human fetal samples and mouse models. The human-specific data will directly test the validity of our working mouse-derived hypotheses regarding the causes these disorders and strengthen the foundation of normal developmental data which will inform our ongoing genetic analyses of human cerebellar malformations. We will conduct the first in-depth analysis of normal human fetal cerebellar development from 4-23 Gestational Weeks, covering major developmental events. We will then examine the pathology of human fetal Dandy-Walker malformation the most common human cerebellar malformation, affecting ~1/3000 live births. Mouse models will be generated in conjunction with these experiments to assess the mechanisms of the developmental pathology. Finally, we will generate the first transcriptome data for normal human fetal cerebellar neurons. These cell-type specific data are critically missing from current publicly available brain resources. Our human fetal cerebellar neuron data will be compared to transcriptome data from existing datasets of endogenous mouse developing cerebellar neurons as well as mES and hPSC-derived cerebellar neurons to development to assess their validity as model systems. Further, the data will also be integrated with exome data from human cerebellar malformation patients to facilitate gene discovery for these important and understudied birth defects.