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

DeSisto, John; O’Rourke, Rebecca; Jones, Hannah; Pawlikowski, Bradley; Malek, Alexandra D.; Bonney, Stephanie; Guimiot, Fabien; Jones, Kenneth L.; Siegenthaler, Julie A.

doi:10.1016/j.devcel.2020.06.009

Cited by 149 publications

(170 citation statements)

References 66 publications

(65 reference statements)

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“…The apical and basal endfeet encounter unique niches, with the latter composed of interneurons, Cajal-Retzius neurons and excitatory neurons. Basal endfeet are tightly connected to a basement membrane, forming a barrier between the brain and the overlying meninges, composed of fibroblasts and blood vessels (DeSisto et al, 2020;Haubst et al, 2006;Myshrall et al, 2012). Along the basal process and at endfeet, dynamic filopodia-like extensions extend and retract, which may influence signaling and neuronal migration (Yokota et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Subcellular mRNA localization and local translation ofArhgap11ain radial glial cells regulates cortical development

Pilaz

Joshi

Liu

et al. 2020

Preprint

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mRNA localization and local translation enable exquisite spatial and temporal control of gene expression, particularly in highly polarized and elongated cells. These features are especially prominent in radial glial cells (RGCs), which serve as neural and glial precursors of the developing cerebral cortex, and scaffolds for migrating neurons. Yet the mechanisms by which distinct sub-cellular compartments of RGCs accomplish their diverse functions are poorly understood. Here, we demonstrate that subcellular RNA localization and translation of the RhoGAP Arhgap11a controls RGC morphology and mediates cortical cytoarchitecture. Arhgap11a mRNA and protein exhibit conserved localization to RGC basal structures in mice and humans, conferred by a 5′UTR cis-element. Proper RGC morphology relies upon active Arhgap11a mRNA transport and localization to basal structures, where ARHGAP11A is locally synthesized. Thus, RhoA activity is spatially and acutely activated via local translation in RGCs to promote neuron positioning and cortical cytoarchitecture. Altogether, our study demonstrates that mRNA localization and local translation mediate compartmentalization of neural progenitor functions to control brain development.

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Section: Introductionmentioning

confidence: 99%

Subcellular mRNA localization and local translation ofArhgap11ain radial glial cells regulates cortical development

Pilaz

Joshi

Liu

et al. 2020

Preprint

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“…This layer most likely represents the dura mater, which was recently shown in a single cell transcriptomic analysis to be enriched for Six1 expression. 18 Paracrine signals from the dura mater contribute to maintenance of suture patency and closure, 19 by coordinating availability of secreted factors such as fibroblast growth factors and β-type transforming growth factors, signalling pathways potentially regulated by SIX1. 20 However, to our knowledge, no genetic mutants have been shown to act primarily by disturbing the dura mater-suture interactions.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Unexpected role ofSIX1variants in craniosynostosis: expanding the phenotype ofSIX1-related disorders

et al. 2021

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BackgroundPathogenic heterozygous SIX1 variants (predominantly missense) occur in branchio-otic syndrome (BOS), but an association with craniosynostosis has not been reported.MethodsWe investigated probands with craniosynostosis of unknown cause using whole exome/genome (n=628) or RNA (n=386) sequencing, and performed targeted resequencing of SIX1 in 615 additional patients. Expression of SIX1 protein in embryonic cranial sutures was examined in the Six1nLacZ/+ reporter mouse.ResultsFrom 1629 unrelated cases with craniosynostosis we identified seven different SIX1 variants (three missense, including two de novo mutations, and four nonsense, one of which was also present in an affected twin). Compared with population data, enrichment of SIX1 loss-of-function variants was highly significant (p=0.00003). All individuals with craniosynostosis had sagittal suture fusion; additionally four had bilambdoid synostosis. Associated BOS features were often attenuated; some carrier relatives appeared non-penetrant. SIX1 is expressed in a layer basal to the calvaria, likely corresponding to the dura mater, and in the mid-sagittal mesenchyme.ConclusionCraniosynostosis is associated with heterozygous SIX1 variants, with possible enrichment of loss-of-function variants compared with classical BOS. We recommend screening of SIX1 in craniosynostosis, particularly when sagittal±lambdoid synostosis and/or any BOS phenotypes are present. These findings highlight the role of SIX1 in cranial suture homeostasis.

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“…Extrasutural tissues were removed to the extent possible to enrich for sutural populations. Cell population identities were determined by reference to published cell type atlases (14)(15)(16)(17)(18) and our previously published study of the murine frontal suture (12).…”

Section: Introductionmentioning

confidence: 99%

Single-cell analysis identifies a key role forHhipin murine coronal suture development

Holmes¹,

Gonzalez‐Reiche

Saturne³

et al. 2021

Preprint

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Craniofacial development depends on proper formation and maintenance of sutures between adjacent bones of the skull. Within sutures, bone growth occurs through proliferation and differentiation of osteoprogenitors to osteoblasts within the osteogenic front at the edge of each bone, and suture mesenchyme maintains the separation between them. Many genes have been found that cause suture dysgenesis when mutated, particularly of the coronal suture. Such genes are largely studied in isolation, and there is little understanding of the overall transcriptional programs within the suture or of the cell populations in which these programs are organized. We performed single-cell and bulk RNA-seq analyses of the murine coronal suture during embryonic development. Replicate libraries at E16.5 and E18.5 were analyzed. We identified 14 cell type populations when both ages were analyzed together. Seven populations at E16.5 and nine at E18.5 comprised the suture mesenchyme, osteogenic fronts, osteoblasts, and associated cell types. We found a distinct coronal suture mesenchyme population at both ages compared to other neurocranial sutures, which was marked by expression of Hhip, an inhibitor of hedgehog signaling. We examined Hhip-/- mice and found a previously unrecognized coronal suture phenotype. At E18.5, Hhip-/- frontal and parietal bones lack the overlap typical of the WT coronal suture. The osteogenic fronts are closely apposed and the suture mesenchyme is depleted, demonstrating that Hhip function is required for normal coronal suture development. Our transcriptomic approach provides a rich resource for further discoveries of potential normal and abnormal developmental relevance.

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

Cited by 149 publications

References 66 publications

Subcellular mRNA localization and local translation ofArhgap11ain radial glial cells regulates cortical development

Subcellular mRNA localization and local translation ofArhgap11ain radial glial cells regulates cortical development

Unexpected role ofSIX1variants in craniosynostosis: expanding the phenotype ofSIX1-related disorders

Single-cell analysis identifies a key role forHhipin murine coronal suture development

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