Roles of engrailed proteins in granule cells during cerebellum development

描述(申请人提供)：小脑是位于后脑上方的后脑结构，协调运动和认知功能。在这项建议中，我的目标是确定导致小脑发育不全的细胞和分子机制，这是由于从发育中的小脑(CB)外生发层(EGL)的颗粒细胞前体(GCP)中去除了(EN)同源框转录因子EN1和EN2(统称为EN1/2)而导致的小脑发育不良。由于在这些突变体中没有检测到主要的细胞结构缺陷，因此必须有其他细胞类型的细胞非自主内稳态伸缩来补偿所产生的颗粒神经元数量的减少。在器官内指定适当数量和位置的细胞类型是发展生物系统的一个关键挑战，无论是对该器官的内在功能还是对该器官在整个有机体内的运作都是如此。在神经系统中，神经元亚型种群大小的变化会影响突触后和突触前神经元的规格或存活，这一影响首先由Viktor Hamburger和Rita Levi-Montalcini发现的现已成为经典的神经营养假说证明。通过对许多疾病，如小头症、精神分裂症和自闭症谱系障碍的脑区大小变化的观察，特别强调了大小调节在神经发育中的重要性。该研究涉及两个主要目的：1)确定EN1/2在CB GCP中调控的细胞过程以及EN1/2突变体GCP对主要有丝分裂原Sonic Hedgehog(SHH)的反应性；2)确定EN2直接DNA结合序列和受EN1/2调控的相关基因，它们是发育中CB中EN1/2调控GCP行为的下游效应因子。

DESCRIPTION (provided by applicant): The cerebellum is a posterior brain structure located above the hindbrain that coordinates motor and cognitive function. In this proposal, I aim to determine the cellular and molecular mechanism responsible for the cerebellar hypoplasia that results from removal of the engrailed (EN) homeobox transcription factors EN1 and EN2 (refered to together as EN1/2) from granule cell progenitors (GCPs) in the external germinal layer (EGL) of the developing cerebellum (Cb). Since major cytoarchitectural defects are not detected in these mutants, there must be cell non-autonomous homeostatic scaling of other cell types to compensate for the reduced granule neuron population generated. Specification of cell types in appropriate number and position within an organ represents a key challenge in development of biological systems, both for the intrinsic function of that organ and with regards to operation of that organ within the whole organism. In neural systems, changes in the population size of neuron subtypes can affect specification or survival of post- and presynaptic neurons, an effect first demonstrated by the now classic neurotrophic hypothesis discovered by Viktor Hamburger and Rita Levi-Montalcini. The importance of size regulation in neural development is particularly emphasized by the observation of changes in brain subregion size in numerous diseases, such as microcephaly, schizophrenia and autism spectrum disorder. The proposed study involves two major aims: 1) determine the cellular processes regulated by EN1/2 in GCPs of the Cb and the responsiveness of EN1/2 mutant GCPs to the major mitogen Sonic Hedgehog (SHH); and 2) identify EN2 direct DNA binding sequences and associated genes regulated by EN1/2 that are downstream effectors of EN1/2 regulated GCP behaviors in the developing Cb.