PT  - JOURNAL ARTICLE
AU  - John DeSisto
AU  - Rebecca O’Rourke
AU  - Stephanie Bonney
AU  - Hannah E. Jones
AU  - Fabien Guimiot
AU  - Kenneth L. Jones
AU  - Julie A. Siegenthaler
TI  - A cellular atlas of the developing meninges reveals meningeal fibroblast diversity and function
AID  - 10.1101/648642
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 648642
4099  - http://biorxiv.org/content/early/2019/05/24/648642.short
4100  - http://biorxiv.org/content/early/2019/05/24/648642.full
AB  - The meninges, a multilayered structure that encases the CNS, is composed mostly of fibroblasts, along with vascular and immune cells. Meningeal fibroblasts are a vital source of signals that control neuronal migration and neurogenesis yet strikingly little is known about their development. We used single cell RNA sequencing to generate a cellular atlas of embryonic meningeal fibroblasts in control and Foxc1-KO mice in which severe CNS defects arise from failed meningeal fibroblast development. We report unique transcriptional signatures for dura, arachnoid and pial fibroblasts and identify S100a6 as the first unique marker of the pial layer. We describe a new meningeal fibroblast subtype marked by µ-Crystallin expression and show these cell types and markers are conserved in human fetal meninges. Our analysis demonstrates layer specific production of extracellular matrix components, transporter expression, and synthesis of secreted factors. Lastly, the cellular atlas of Foxc1-KO meninges provides insight into their severe phenotype, confirming a massive loss in arachnoid and dura fibroblasts and Foxc1-KO pial fibroblasts are so altered that they cluster as a different cell type based on gene expression. These studies provide an unprecedented view of meningeal fibroblast development, highlighting unexpected fibroblast diversity and function, while providing mechanistic insights into the meninges role in CNS development.