ISDN2014_0119: Mesenchymal Foxc1 non‐autonomously controls cerebellar development through SDF1α‐CXCR4 maintenance of radial glial cells

Haldipur, Parthiv; Gillies, Gwendolyn S; Janson, Olivia K; Chizhikov, Victor V.; Millen, Kathleen J.

doi:10.1016/j.ijdevneu.2015.04.097

Cited by 4 publications

(3 citation statements)

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“…Meningeal fibroblasts have emerged as critical players in CNS development (reviewed in (Dasgupta and Jeong, 2019;Siegenthaler and Pleasure, 2011). They are the major source of basement 48 membrane (BM) proteins that form the glial limitans (Hecht, et al, 2010a;Halfter, et al, 2002;Hartmann, 49 et al, 1992), and meninges-derived Cxcl12 is required for migration of Cajal-Retzius cells (Borrell and 50 Marin, 2006), proliferation of cerebellar radial glial progenitor cells (Haldipur, et al, 2015;Haldipur, et 51 al., 2014) and proper positioning of granule cell progenitors in the hippocampus and cerebellum (Reiss, 52 et al, 2002;Zhu, et al, 2002). Bmps produced by the meninges help control cortical layer formation (Choe 53 and Pleasure, 2018; Choe, et al, 2012), while meningeal fibroblast production of retinoic acid directs 54 cortical neurogenesis and cerebrovascular development (Boucherie, et al, 2018;Haushalter, et al, 2017;55 Mishra, et al, 2016;Siegenthaler, et al, 2009b).…”

Section: Introduction 43mentioning

confidence: 99%

“…Col1a1-GFP is a well 86 characterized transgenic mouse line and labels meningeal fibroblasts (Kelly, et al, 2016; Soderblom, et 87 al., 2013). We chose to analyze only the telencephalic meninges as this region of the meninges is most 88 affected in Foxc1 mutants (Haldipur, et al, 2015; Siegenthaler, et al, 2009b). We used flow cytometry to 89 sort GFP+ cells from the dissected telencephalic meninges of a single embryo and executed single cell 90 capture and sequencing of 2943 cells using the 10X Genomics platform.…”

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confidence: 99%

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

DeSisto¹,

O’Rourke²,

Bonney³

et al. 2019

Preprint

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21 22 Key words (3-6 words): brain development, meninges, pial basement membrane, retinoic acid, human 23 meninges 24 2 Abstract 25The meninges, a multilayered structure that encases the CNS, is composed mostly of fibroblasts, 26 along with vascular and immune cells. Meningeal fibroblasts are a vital source of signals that control 27 neuronal migration and neurogenesis yet strikingly little is known about their development. We used 28 single cell RNA sequencing to generate a cellular atlas of embryonic meningeal fibroblasts in control and 29 Foxc1-KO mice in which severe CNS defects arise from failed meningeal fibroblast development. We 30 report unique transcriptional signatures for dura, arachnoid and pial fibroblasts and identify S100a6 as the 31 first unique marker of the pial layer. We describe a new meningeal fibroblast subtype marked by µ-32Crystallin expression and show these cell types and markers are conserved in human fetal meninges. Our 33 analysis demonstrates layer specific production of extracellular matrix components, transporter 34 expression, and synthesis of secreted factors. Lastly, the cellular atlas of Foxc1-KO meninges provides 35 insight into their severe phenotype, confirming a massive loss in arachnoid and dura fibroblasts and Foxc1-36 KO pial fibroblasts are so altered that they cluster as a different cell type based on gene expression. These 37 studies provide an unprecedented view of meningeal fibroblast development, highlighting unexpected 38 fibroblast diversity and function, while providing mechanistic insights into the meninges role in CNS 39 development. 40 41 42 4 of these specialized fibroblasts, mechanisms that guide their development, and their functions in the 68 developing and adult brain. 69Here we present single cell RNA sequencing (scRNA-seq) analysis of E14.5 mouse telencephalic 70 meningeal fibroblasts from control and Foxc1-KO mice. We define the transcriptional signatures of 71 embryonic pial, arachnoid and dural fibroblasts, including identification of a first-ever pial fibroblast 72 marker, S100a6. We present evidence for a previously unknown subtype of meningeal fibroblast we term 73 ceiling cells, so named as the meninges are like a 'ceiling' for the brain, that are enriched for expression 74 of µ-Crystallin. We show that our novel markers for the pia (S100a6), the arachnoid (CRABP2) and 75 ceiling cells (µ-Crystallin) in mouse identify specific meningeal populations in the human fetal brain, 76 indicating development of meningeal fibroblasts is conserved between mouse and human. ScRNA-seq 77 and cluster analysis of the Foxc1-KO meninges fibroblasts revealed a near absence of pial, arachnoid and 78 dural fibroblasts and, rather unexpectedly, a pial-like meningeal fibroblast population that clustered 79 separately in the single cell data analysis. We believe our single cell analyses of the embryonic meningeal 80 fibroblasts will provide a valuable resource that will aid in the study of embryonic and, possibly, the adult 81 meningeal fibroblast populations. 82Resul...

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Section: Introduction 43mentioning

confidence: 99%

mentioning

confidence: 99%

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

DeSisto¹,

O’Rourke²,

Bonney³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The meninges play several key roles in brain development and Foxc1 is required for meninges function (Aldinger et al, 2009; Haldipur et al, 2015; Haldipur et al, 2014; Hecht et al, 2010; Siegenthaler et al, 2009; Zarbalis et al, 2012; Zarbalis et al, 2007). In the Foxc1 mutant telencephalon, formation of the neural crest-derived meninges that overlay the neocortex is severely impaired and this results in a reduction of meningeal-derived cues required for normal development of the neocortex (Harrison-Uy and Pleasure, 2012; Hecht et al, 2010; Siegenthaler et al, 2009; Zarbalis et al, 2012; Zarbalis et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF—A pathways downstream of retinoic acid from the meninges

Mishra

Choe

Pleasure

et al. 2016

Developmental Biology

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Growth and maturation of the cerebrovasculature is a vital event in neocortical development however mechanisms that control cerebrovascular development remain poorly understood. Mutations in or deletions that include the FOXC1 gene are associated with congenital cerebrovascular anomalies and increased stroke risk in patients. Foxc1 mutant mice display severe cerebrovascular hemorrhage at late gestational ages. While these data demonstrate Foxc1 is required for cerebrovascular development, its broad expression in the brain vasculature combined with Foxc1 mutant’s complex developmental defects have made it difficult to pinpoint its function(s). Using global and conditional Foxc1 mutants, we find 1) significant cerebrovascular growth defects precede cerebral hemorrhage and 2) expression of Foxc1 in neural crest-derived meninges and brain pericytes, though not endothelial cells, is required for normal cerebrovascular development. We provide evidence that reduced levels of meninges-derived retinoic acid (RA), caused by defects in meninges formation in Foxc1 mutants, is a major contributing factor to the cerebrovascular growth defects in Foxc1 mutants. We provide data that suggests that meninges-derived RA ensures adequate growth of the neocortical vasculature via regulating expression of WNT pathway proteins and neural progenitor derived-VEGF-A. Our findings offer the first evidence for a role of the meninges in brain vascular development and provide new insight into potential causes of cerebrovascular defects in patients with FOXC1 mutations.

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Single-Cell Transcriptomic Analyses of the Developing Meninges Reveal Meningeal Fibroblast Diversity and Function

et al. 2020

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ISDN2014_0119: Mesenchymal Foxc1 non‐autonomously controls cerebellar development through SDF1α‐CXCR4 maintenance of radial glial cells

Cited by 4 publications

References 0 publications

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

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

Cerebrovascular defects in Foxc1 mutants correlate with aberrant WNT and VEGF—A pathways downstream of retinoic acid from the meninges

Single-Cell Transcriptomic Analyses of the Developing Meninges Reveal Meningeal Fibroblast Diversity and Function

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