Formation and Function of the Meninges

项目总结 脑膜从中枢神经系统发育的最早阶段就包裹着它，并作为一种保护性物质持续存在。 为成人中枢神经系统做掩护。许多研究表明，脑膜，特别是脑膜成纤维细胞，具有重要的 人类发育中神经发生、神经元迁移和先天缺陷的调控作用 脑膜缺陷可能导致大脑发育。脑膜还含有独特的免疫和 现在已知在神经免疫中起关键作用的血管细胞群(血液和淋巴管) 监测、脑脊液引流和中枢神经系统废物清除，从而支持中枢神经系统的整体健康和 功能。尽管如此，我们对细胞和分子机制的了解还不完全 控制脑膜的形成。我们对不同的成纤维细胞的发育知之甚少。 产生有助于控制大脑发育的因子并可能在脑发育中发挥作用的人群 其他脑膜细胞类型(免疫细胞)和邻近结构，如头盖骨。我们之前的工作 显示前脑周围软脑膜层、蛛网膜层和硬脑膜层的脑膜成纤维细胞群 在转录上是独一无二的，在大脑发育的早期阶段就开始表达层特异性标记。 我们和其他人之前已经证明，转录因子Foxc1是这一脑膜层的关键 规格。在这里，我们建议使用一种新的脑膜条件性Foxc1小鼠突变体与 单细胞转录组学(ScRNAseq)开始鉴定：1)正常发育进程 脑膜成纤维细胞层细胞并确定导致脑膜发育失败的信号通路。 Foxc1突变体和2)鉴定胎儿期脑膜成纤维细胞产生的控制成熟度的信号 其他脑膜群，特别是免疫细胞，以及邻近的头盖骨。完成 这里概述的实验将作为未来赠款申请的基础试点数据，支持我们的长期 学期研究的目标对研究脑膜对中枢神经系统发育和功能的控制将是一个重要的 研究人员研究脑膜相关结构、过程、疾病或畸形的资源。

Project summary The meninges encase the CNS from its earliest stages of development and persist as a protective covering for the adult CNS. Many studies show the meninges, in particular the meningeal fibroblasts, has vital roles in controlling developmental neurogenesis and neuronal migration and congenital defects in human brain development can arise from meningeal defects. The meninges also contain unique immune and vascular cell populations (blood and lymphatics) that are now known to serve key functions in neuro-immune surveillance, cerebrospinal fluid drainage and CNS waste removal, thus supporting overall CNS health and function. Despite this, we have an incomplete understanding of the cellular and molecular mechanisms that control formation of the meninges. We know very little about the development of the different fibroblast populations that produce factors that help control brain development and may have roles in development of other meninges cell types (immune cells) and adjacent structures like the calvarium. Our prior work demonstrates that meningeal fibroblast populations of the pia, arachnoid and dura layers around the forebrain are transcriptionally unique and begin to express layer specific markers at early stages of brain development. We and others have previously shown that the transcription factor Foxc1 is key for this meningeal layer specification. Here we propose to use a new, meninges conditional Foxc1 mouse mutant in combination with single cell transcriptomics (scRNAseq) to begin to identify: 1) the normal developmental progression of meningeal fibroblast layer populations and identify signaling pathways that underlie the failed development in Foxc1 mutants and 2) identify signals produced by prenatal meningeal fibroblasts that control maturation of other meningeal populations, in particular immune cells, and the adjacent calvarium. Completion of experiments outlined here will serve as foundational pilot data for future grant applications, support our long- term research goals in studying meninges control of CNS development and function and will be an important resource for researchers studying meninges-related structure, process, disease or malformation.