Delta-Notch Signaling by Intermediate Neuronal Progenitors: Live Imaging

描述（由申请人提供）：大脑皮层对大脑的高级运动、感觉和认知功能至关重要，如社会互动和交流，并与边缘系统的皮层下区域一起调节复杂的情绪和动机行为。皮层发育障碍是自闭症、精神分裂症和抑郁症等神经精神疾病的基础，而皮层和边缘回路的异常发育轨迹可能影响药物滥用等适应性行为。本研究的目的是研究调节大脑皮层正常神经元产生的分子和细胞机制，这些神经元产生于位于新皮层心室区的异质干细胞/祖细胞群，对正确的神经回路轨迹至关重要。在皮质发生过程中，由Delta-Notch信号介导的细胞间相互作用是产生正确数量的神经元和维持祖细胞池所必需的，尽管基本细节尚不清楚。重要的是，不同细胞类型之间的特定细胞和分子相互作用尚未被描述。我们假设不同的细胞类型通过进化多样的Delta-Notch基因家族组分相互传递信号，并且一种新的delta介导的祖细胞亚群之间的相互作用控制着神经元产生和祖细胞维持之间的平衡。我们将首先利用原位杂交/免疫标记技术结合特定细胞类型的转基因标记，确定表达不同Delta-Notch信号成分的皮层细胞类型。我们开发了一种新的双色双光子活细胞成像技术，作为一项重大创新，使我们能够确定动态行为细胞中Delta-Notch信号转导的细胞基础，这将在功能实验中进行测试。这项探索性R21资助的结果将为我们提出的一个复杂的新模型提供基础，该模型涵盖了发育中的皮层中多种Delta-Notch信号调节的细胞-细胞相互作用的多种来源。未来的研究将在发育中的皮层下区域以及青少年和成人神经发生中研究这种机制。公共卫生相关性：神经和行为疾病和障碍，如自闭症、精神分裂症和药物滥用易感性，被认为是由大脑神经元的产生/轨迹/连接的发育缺陷引起的。如果我们知道这些神经元是如何正常发育的，那么当它们的正常发育出现问题时，我们就能更好地制定出修复或替换它们的策略。

DESCRIPTION (provided by applicant): The cerebral cortex is critically important for higher motor, sensory, and cognitive functions of the brain, such as social interactions and communication, and together with subcortical areas of the limbic system, regulate complex emotional and motivated behaviors. Disorders of cortical development underlie neuropsychiatric illnesses such as autism, schizophrenia, and depression, and the abnormal developmental trajectories of cortical and limbic circuits may impact adaptive behaviors such as drug abuse. The objective of this proposal is to investigate the molecular and cellular mechanisms regulating the normal production of neurons in the cerebral cortex, which arise from a heterogeneous population of stem/progenitor cells located in the ventricular zone of the neocortex and essential for correct neural circuit trajectories. Cell-cell interactions mediated by Delta-Notch signaling are required for both producing the correct number of neurons and maintaining the progenitor pool during corticogenesis, although essential details remain unknown. Importantly, the specific cellular and molecular interactions between different cell types have not been delineated. We hypothesize that different cell types signal to each other through evolutionary diversified components of Delta-Notch gene families, and that a novel Delta-mediated interaction between a subset of progenitors controls the balance between neuron production and progenitor maintenance. We will first determine the cortical cell types that express different Delta-Notch signaling components using combined in situ hybridization/immunolabeling techniques in conjunction with transgenic markers of defined cell types. We have developed a novel 2-color 2-photon live-cell imaging technique that serves as major innovation, allowing us to determine the cellular basis of Delta-Notch signal transduction in dynamically behaving cells that will be tested in functional experiments. The results of this exploratory R21 grant will provide the foundation of a sophisticated new model we propose that encompasses multiple sources of cell-cell interactions regulated by diverse Delta-Notch signaling in the developing cortex. Future studies will examine this mechanism in developing subcortical regions, and in adolescent and adult neurogenesis. PUBLIC HEALTH RELEVANCE: Neurological and behavioral diseases and disorders, such as autism, schizophrenia and susceptibility to drug abuse are thought to arise from developmental deficits in the generation/trajectory/connectivity of neurons in the brain. If we know how these neurons normally develop, then we will be better able to develop strategies aimed at repairing or replacing them when their normal development goes awry.