Meninges Specification and Cellular Crosstalk to the Developing Brain

项目总结 中枢神经系统(CNS)的发展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，它实质上影响 大脑发育，在很大程度上是通过分泌因子来引导神经元迁移和神经发生。这是 在带有FOXC1突变的小鼠和人类身上观察到的中枢神经系统发育的显著缺陷， 一种转录因子，由脑膜成纤维细胞表达，但不表达任何神经细胞。不管剩下多少 尚不清楚脑膜因子如何激活或抑制神经细胞中的分子信号通路 影响发育过程。填补这些知识空白将显著提高我们的 了解脑膜的稳态功能和神经发育过程中的病理变化 精神错乱。Foxc1突变体在前脑上方没有正常的脑膜成纤维细胞，而是增加了顶端 祖细胞自我更新和神经元产生减少导致新皮质延长，部分与缺乏有关 脑膜中的维甲酸。然而，目前尚不清楚在foxc1突变体中有哪些异常信号通路。 顶端祖细胞促进自我更新的增加及其与脑膜衍生的减少之间的关系 像维甲酸这样的因素。这项建议的目的是调查脑膜衍生因子是如何调节 控制大脑皮层神经发生的分子信号。利用空间转录技术对胚胎Foxc1- KO组织切片，我在Foxc1中发现了Notch信号的上调，已知可以促进干细胞的自我更新 KO新皮质祖细胞。在目标1中，我将使用全局和有针对性的方法来抑制Notch信令 Foxc1-KO动物，并测试这是否改善了这些突变体中的新皮质神经发生。在《目标2》中，我将测试 脑膜衍生维甲酸或脑膜产生的其他因子调节Notch信号转导 新皮质祖细胞促进神经发生。该项目的结果将提供重要的洞察力 脑膜的分子机制--正常发育所需的大脑信号。

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.