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A cellular atlas of the developing meninges reveals meningeal fibroblast diversity and function

John DeSisto, Rebecca O’Rourke, Stephanie Bonney, Hannah E. Jones, Fabien Guimiot, Kenneth L. Jones, View ORCID ProfileJulie A. Siegenthaler
doi: https://doi.org/10.1101/648642
John DeSisto
1Department of Pediatrics Section of Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 USA
2Department of Pediatrics Section of Section of Hematology, Oncology, Bone Marrow Transplant, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 USA
3Cell Biology, Stem Cells and Development Graduate Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 USA
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Rebecca O’Rourke
2Department of Pediatrics Section of Section of Hematology, Oncology, Bone Marrow Transplant, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 USA
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Stephanie Bonney
1Department of Pediatrics Section of Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 USA
3Cell Biology, Stem Cells and Development Graduate Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 USA
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Hannah E. Jones
1Department of Pediatrics Section of Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 USA
3Cell Biology, Stem Cells and Development Graduate Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 USA
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Fabien Guimiot
4INSERM UMR 1141, Hôpital Robert Debré, 75019 Paris, France
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Kenneth L. Jones
2Department of Pediatrics Section of Section of Hematology, Oncology, Bone Marrow Transplant, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 USA
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Julie A. Siegenthaler
1Department of Pediatrics Section of Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 USA
3Cell Biology, Stem Cells and Development Graduate Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045 USA
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  • ORCID record for Julie A. Siegenthaler
  • For correspondence: julie.siegenthaler@ucdenver.edu
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Abstract

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.

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Posted May 24, 2019.
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A cellular atlas of the developing meninges reveals meningeal fibroblast diversity and function
John DeSisto, Rebecca O’Rourke, Stephanie Bonney, Hannah E. Jones, Fabien Guimiot, Kenneth L. Jones, Julie A. Siegenthaler
bioRxiv 648642; doi: https://doi.org/10.1101/648642
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A cellular atlas of the developing meninges reveals meningeal fibroblast diversity and function
John DeSisto, Rebecca O’Rourke, Stephanie Bonney, Hannah E. Jones, Fabien Guimiot, Kenneth L. Jones, Julie A. Siegenthaler
bioRxiv 648642; doi: https://doi.org/10.1101/648642

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