Meninges Specification and Cellular Crosstalk to the Developing Brain

项目摘要 中枢神经系统（CNS）的发育需要细胞间精确的“串扰”， 神经细胞和非神经细胞。脑膜中的成纤维细胞是一种非神经细胞， 大脑发育，在很大程度上通过分泌的因子，引导神经元迁移和神经发生。这是 通过在FOXC 1突变的小鼠和人类中观察到的CNS发育的显著缺陷来强调， 一种由脑膜成纤维细胞表达而非任何神经细胞的转录因子。不管剩下多少 尚不清楚脑膜中的因子如何激活或抑制神经细胞中的分子信号通路， 影响发展进程。填补这些知识空白将大大提高我们的 了解脑膜的稳态功能和神经发育中发生的病理学 紊乱Foxc 1突变体在前脑没有正常的脑膜成纤维细胞， 祖细胞自我更新和减少神经元产生导致新皮层延长，部分与缺乏 脑膜衍生的视黄酸。然而，目前还不清楚Foxc 1突变体中异常的信号通路是什么， 顶端祖细胞促进自我更新的增加，以及这是如何与脑膜衍生的减少有关的。 像维甲酸这样的因素。这个提议的目的是研究脑膜衍生因子如何调节 控制新皮层神经发生的分子信号。利用空间转录组学对胚胎Foxc 1- KO组织切片，我已经确定了升高的Notch信号，已知促进干细胞自我更新，在Foxc 1- KO新皮质祖细胞。在目标1中，我将使用全局和靶向方法抑制Notch信号传导， Foxc 1-KO动物，并测试这是否改善了这些突变体中的新皮层神经发生。在目标2中，我将测试 脑膜衍生的视黄酸或由脑膜产生的其它因子调节Notch信号传导， 新皮质祖细胞促进神经发生。该项目的结果将提供重要的见解， 正常发育所需的脑膜-大脑信号传导的分子机制。

PROJECT SUMMARY Development of the central nervous system (CNS) requires precise intercellular ‘crosstalk’ between neural cells and non-neural cells. Fibroblasts in the meninges are a non-neural cell that substantially influences brain development, in large part via secreted factors that guide neuronal migration and neurogenesis. This is underscored by significant defects in CNS development observed in mice and humans with mutations in FOXC1, a transcription factor expressed by meningeal fibroblasts but not any neural cells. However much remains unknown about how factors from the meninges activate or inhibit molecular signaling pathways in neural cells to influence developmental processes. Filling these gaps in knowledge would significantly improve our understanding of the homeostatic function of the meninges and the pathology that occurs in neurodevelopmental disorders. Foxc1 mutants do not have normal meningeal fibroblasts over the forebrain, have increased apical progenitor self-renewal and reduced neuron production leading to neocortical lengthening, linked in part to lack of meninges derived retinoic acid. However, it is not known what aberrant signaling pathways in Foxc1 mutant apical progenitors promote increased self-renewal and how this is connected to a reduction of meninges derived factors like retinoic acid. The objective of this proposal is to investigate how meninges derived factors regulate molecular signaling to control neurogenesis in the neocortex. Using spatial transcriptomics on embryonic Foxc1- KO tissue sections, I have identified elevated Notch signaling, known to promote stem cell self-renewal, in Foxc1- KO neocortical progenitors. In Aim 1, I will use global and targeted approaches to inhibit Notch signaling in Foxc1-KO animals and test if this improves neocortical neurogenesis in these mutants. In Aim 2, I will test is meningeal derived retinoic acid or other factors produced by the meninges modulate Notch signaling in neocortical progenitors to promote neurogenesis. Results from this project will provide important insight into molecular mechanisms for meninges-brain signaling required for normal development.