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.

脑膜从中枢神经系统发育的最早阶段起就包裹着它，并一直作为 成人的大脑。许多研究表明，脑膜在控制发育中的神经发生方面具有重要作用。 脑膜缺陷可能导致人类大脑发育中的神经元迁移和先天缺陷。 尽管如此，控制脑膜形成的细胞和分子机制主要是 未知。脑膜研究进展的一个主要限制是缺乏现代的、分子的 脑膜成纤维细胞和发育中脑膜的其他重要细胞残留物的特征。 由于脑膜成纤维细胞与血管和免疫细胞混合在一起，这一点很难获得。 这限制了对发育中的脑膜进行“大量”转录或蛋白质组学分析的用处。 为了克服这些障碍，我们将使用单细胞RNA测序以及Col1a1-GFP小鼠品系 我们已经发现可以用来丰富脑膜成纤维细胞。在本提案中，我们将使用这些 缺乏转录因子Foxc1的小鼠的技术，我们和其他人之前证明是必需的 用于脑膜的发育和功能。这些数据将被用来1)创建所有 发育过程中的脑膜细胞群体和2)确定这些群体中的基因表达 脑膜发育受损的Foxc1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， 建立血液和淋巴神经丛、免疫细胞群，并最终建立神经干细胞 利基市场。对于我们关注Foxc1很重要，我们将获得Foxc1损失对以下各项影响的单元格分辨率 分离的脑膜成纤维细胞群。由此，我们可以提出关于Foxc1如何丢失的新假说 损害脑膜层的发育和功能，这对大脑发育是如此具有破坏性。最后， 这些数据将提供急需的脑膜特征，为研究人员提供资源 研究与脑膜有关的结构、过程、疾病或畸形。