Foxc1 control of meninges formation and function

Foxc1 控制脑膜形成和功能

• 批准号: 9769908
• 负责人: Julie Siegenthaler
• 金额: $ 7.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769908
• 关键词: Adult; Basement membrane; Blood; Blood Vessels; Brain; Cells; Cellular Structures; Cerebrum; Cluster Analysis; Complex; Congenital Abnormality; Data; Data Set; Defect; Development; Disease; Embryo; Ensure; FOXC1 gene; FOXC2 gene; Failure; Fibroblasts; Future; Gene Expression; Gene Expression Alteration; Genetic Transcription; Goals; Health; Heterogeneity; Homing; Human; Immune; Impaired cognition; Impairment; Knowledge; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Meningeal; Meninges; Modernization; Molecular; Molecular Profiling; Mus; Mutant Strains Mice; Mutation; Neocortex; Neuraxis; Neurodevelopmental Disorder; Neurons; Pathway interactions; Patients; Pericytes; Population; Process; Proteins; Proteomics; Research Personnel; Resolution; Resources; Role; Signal Pathway; Signal Transduction; Source; Structure; Techniques; Testing; Therapeutic; Tretinoin; base; brain malformation; cell type; cerebrovascular; experimental study; malformation; migration; motor impairment; mutant; neocortical; nerve stem cell; nervous system development; neurogenesis; novel marker; single-cell RNA sequencing; stem cell niche; transcription factor; transcriptomics

The meninges encase the CNS from its earliest stages of development and persist as a protective covering for the adult brain. Many studies show the meninges have vital roles in controlling developmental neurogenesis and neuronal migration and congenital defects in human brain development can arise from meningeal defects. Despite this, the cellular and molecular mechanisms that control formation of the meninges are largely unknown. A major limitation to progress on studying the meninges is lack of modern, molecular characterization of meningeal fibroblasts and other important cellular residents of the developing meninges. This has been difficult to obtain due to the intermingling of meningeal fibroblasts with vascular and immune cell populations, limiting the usefulness of `bulk' transcriptional or proteomic analysis of the developing meninges. To overcome these obstacles, we will use single-cell RNA-sequencing along with the Col1a1-GFP mouse line that we have found can be used to enrich for meningeal fibroblasts. In this proposal, we will use these techniques with mice that lack the transcription factor Foxc1, previously shown by us and others to be required for meninges development and function. This data will be used to 1) create a molecular signature of all meningeal cell populations during development and 2) identify how gene expression in these populations changes in Foxc1 mutants in which meningeal development is impaired. This approach will provide important knowledge of meninges `assembly', a complex process that includes formation of the fibroblast layers, the establishment of blood and lymphatic plexuses, immune cell populations and, eventually, a neural stem cell niche. Important for our focus on Foxc1, we will obtain single cell resolution of the impact of Foxc1 loss on separate meningeal fibroblast populations. From this we can develop new hypotheses about how loss of Foxc1 impairs development and function of the meningeal layers that is so devastating to brain development. Finally, these data will provide much needed characterization of the meninges that can be a resource for researchers studying meninges-related structure, process, disease or malformation.

脑膜从CNS发育的最早阶段起就包裹着CNS，并作为CNS的保护性覆盖物持续存在。 成人大脑许多研究表明脑膜在控制发育神经发生中起着重要作用 并且脑膜缺陷可引起人脑发育中的神经元迁移和先天性缺陷。 尽管如此，控制脑膜形成的细胞和分子机制在很大程度上 未知脑膜研究进展的一个主要限制是缺乏现代分子生物学手段， 脑膜成纤维细胞和发育中脑膜的其他重要细胞居民的表征。 由于脑膜成纤维细胞与血管和免疫细胞的混合， 群体，限制了“批量”转录或蛋白质组学分析的有用性的发展脑膜。 为了克服这些障碍，我们将使用单细胞RNA测序沿着Col 1a 1-GFP小鼠系 我们发现可以用来富集脑膜成纤维细胞。在本提案中，我们将使用这些 用缺乏转录因子Foxc 1的小鼠进行的技术，我们和其他人先前已经证明， 对于脑膜的发育和功能。这些数据将用于1）创建所有的分子签名 脑膜细胞群体在发展和2）确定如何在这些群体中的基因表达 脑膜发育受损的Foxc 1突变体的变化。这种方法将提供重要的 脑膜“组装”的知识，这是一个复杂的过程，包括成纤维细胞层的形成， 建立血液和淋巴丛，免疫细胞群，最终，神经干细胞 利基对于我们关注Foxc 1很重要的是，我们将获得Foxc 1缺失对细胞的影响的单细胞分辨率。 分离脑膜成纤维细胞群。由此，我们可以发展新的假设，即Foxc 1的丢失是如何导致 损害脑膜层的发育和功能，这对大脑发育是毁灭性的。最后， 这些数据将为研究人员提供急需的脑膜特征， 研究脑膜相关的结构、过程、疾病或畸形。