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Meningeal-derived retinoic acid regulates neurogenesis via suppression of Notch and Sox2 [CUT&Run]

ABSTRACT: During development, the meninges act as a regulator of neocortical development by secreting ligands that act on neural cells to regulate neurogenesis and neuronal migration. Meninges-derived retinoic acid (RA) promotes neocortical progenitor cell cycle exit however the underlying mechanism is unknown. Here, we use Foxc1-mutant embryos that lack meninges-derived ligands, spatial transcriptomics, and profiling of retinoic-acid receptor-a (RARa) DNA binding to identify the neurogenic transcriptional mechanisms of RA signaling in cortical neural progenitors. We determined that meningeal-derived RA controls neurogenesis by suppressing self-renewal pathways Notch signaling and the transcription factor Sox2. We show that RARα binds in the Sox2ot promoter, a long non-coding RNA that regulates Sox2 expression, and RA promotes Sox2ot expression in neocortical progenitors. Our findings elucidate a previously unknown mechanism of howmeningeal RA coordinates neocortical development and insight into how defects in meningeal develop can cause neurodevelopmental disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE269282 | GEO | 2024/09/25

REPOSITORIES: GEO

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Meningeal-derived retinoic acid regulates neurogenesis via suppression of Notch and Sox2 [Spatial Transcriptomics]

Project description:During development, the meninges act as a regulator of neocortical development by secreting ligands that act on neural cells to regulate neurogenesis and neuronal migration. Meninges-derived retinoic acid (RA) promotes neocortical progenitor cell cycle exit however the underlying mechanism is unknown. Here, we use Foxc1-mutant embryos that lack meninges-derived ligands, spatial transcriptomics, and profiling of retinoic-acid receptor-a (RARa) DNA binding to identify the neurogenic transcriptional mechanisms of RA signaling in cortical neural progenitors. We determined that meningeal-derived RA controls neurogenesis by suppressing self-renewal pathways Notch signaling and the transcription factor Sox2. We show that RARα binds in the Sox2ot promoter, a long non-coding RNA that regulates Sox2 expression, and RA promotes Sox2ot expression in neocortical progenitors. Our findings elucidate a previously unknown mechanism of howmeningeal RA coordinates neocortical development and insight into how defects in meningeal develop can cause neurodevelopmental disorders.

2024-09-25 | GSE269283 | GEO

Meningeal cells contribute to postnatal cortical neurogenesis.

Project description:Postnatal brain neurogenesis in mammals is believed to be restricted to rare germinative remnants of the neuroepithelium. In this study, we discovered that, in the postnatal brain, a subset of embryonically derived progenitors is present in meningeal substructures. These cells migrate from the meningeal substructures to the retrosplenial and visual motor cortex and differentiate into (electrically) functional integrated neurons. Lineage tracing analysis revealed that this subset of neural progenitors originate largely from PDGFR+ cells. PDGFR-derived cells differentiate mostly into Satb2+ neurons in cortical layers I-IV. Thus, a reservoir of embryonically derived progenitors in the meninges contributes to postnatal cerebral cortical neurogenesis.

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Infection drives long-term meningeal engraftment by inflammatory monocytes that impair central nervous system immunity [II]

Project description:Tissue-resident macrophages have an embryonic origin, but are replenished under steady state conditions in some tissues by blood monocytes that can adopt genotypic and phenotypic features of the residents. However, little is known about the residency and functional properties of infiltrating macrophages after an inflammatory challenge. The meninges of the central nervous system (CNS) are populated by a dense network of specialized macrophages that act as resident immune sentinels. Here we show that following lymphocytic choriomeningitis virus infection resident meningeal macrophages become activated by innate inflammatory cytokines, acquire viral antigen, and interact directly with infiltrating cytotoxic T lymphocytes (CTL), which leads to their depletion. Concurrently, the meninges are heavily infiltrated by peripherally-derived inflammatory monocytes that engraft the meningeal niche and remain in situ for months after viral clearance. This engraftment leads to phenotypic and functional changes in the pool of resident meningeal macrophages that depends in part on IFNγ signaling. These changes include loss of bacterial and immunoregulatory sensors that impede subsequent CNS immune reactions. Collectively, these data indicate that peripheral monocytes can engraft the meninges after an inflammatory challenge, imprinting the compartment with long-term defects in immune function.

2019-03-06 | GSE108647 | GEO

Infection drives long-term meningeal engraftment by inflammatory monocytes that impair central nervous system immunity [I]

2019-03-06 | GSE108467 | GEO

Single cell transcriptomic analyses of the developing meninges reveal meningeal fibroblast diversity and function

Project description:The meninges are a multilayered structure composed of fibroblasts, blood and lymphatic vessels, and immune cells. Meningeal fibroblasts secrete a variety of factors that control CNS development, yet strikingly little is known about their heterogeneity or development. Using single cell sequencing, we report distinct transcriptional signatures for fibroblasts in the embryonic dura, arachnoid and pial. We define new markers for meningeal layers and show conservation in human meninges. We find that embryonic meningeal fibroblasts are transcriptionally distinct between brain regions and identify a regionally localized pial sub-population marked by expression of µ-Crystallin. Developmental analysis reveals a progressive, ventral to dorsal maturation of telencephalic meninges. Our studies present an unprecedented view of meningeal fibroblasts, providing a molecular profile of embryonic meningeal fibroblasts by layer that yield insights into mechanisms of meninges development and function.

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Meningeal gd T cells regulate anxiety like behaviors via Il17a signaling on Neurons

Project description:By characterizing the meningeal compartment of naive mice, here we explored a unique population of tissue-resident gd T cells, which we found to be the major source of IL-17A in the steady state meninges. gd T cells rapidly harbor meninges at perinatal stages and actively make IL-17A. Their IL-17A production was TCR-dependent but it occurred independent of commensal microbiota. The absence of meningeal gd T cells was related with risk-taking behavior in mice, which was dependent on the IL-17A signaling directly in the prefrontal cortex neurons. Our results demonstrate that tissue-resident meningeal gd T cell-derived IL-17A may represent an evolutionary bridge between anti-pathogen response and avoidance behavioral traits in vertebrates.

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CNS antigen-specific control of early B-lineage development in the meninges

Project description:In this work we report that early developing B cells present in the meninges of mice at all ages. Single cell RNA-sequencing (scRNA-seq) analysis revealed a consecutive trajectory of meningeal developing B cells in mice and non-human primates (NHPs). Parabiosis together with lineage tracing of hematopoietic stem cells (HSCs) showed that meningeal developing B cells are continuously replenished from the HSC-derived progenitors via a circulation-independent route. Importantly, autoreactive immature B cells which recognize myelin oligodendrocyte glycoprotein (MOG), a central nervous system (CNS)-specific antigen, are eliminated from the meninges but not BM. Furthermore, genetic deletion of MOG tolerated the development/presence/residence of self-reactive B cells in the meninges. Thus, we propose that meninges function as a unique reservoir for B cell development, allowing in situ negative selection of CNS-antigen-autoreactive B cell clones to ensure a local non-self-reactive immune repertoire.

2021-11-01 | GSE176263 | GEO

Bacteria hijack a neuro-immune axis in meninges to facilitate brain invasion

Project description:The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. How pain and neuro-immune interactions impact meningeal host defenses is unclear. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system (CNS), affecting over one million people a year. Here we find that Nav1.8+ neuron signaling to immune cells in the meninges via the neuropeptide calcitonin gene-related peptide (CGRP) exacerbates bacterial meningitis. Nociceptor ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors via Pneumolysin to release CGRP, which acts through its receptor RAMP1 on meningeal macrophages to inhibit chemokine expression, neutrophil recruitment and antimicrobial defenses. Macrophage-specific RAMP1 deficiency or blockade of RAMP1 signaling enhanced immune responses and bacterial clearance in meninges and brain. Therefore, targeting a neuro-immune axis in the meninges can enhance host defenses and may be a potential treatment for bacterial meningitis.

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Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury

Project description:The meningeal space is occupied by a diverse repertoire of innate and adaptive immune cells. CNS injury elicits a rapid immune response that affects neuronal survival and recovery, but the role of meningeal inflammation in CNS injury remains poorly understood. Here we describe group 2 innate lymphoid cells (ILC2s) as a novel cell type resident in the healthy meninges that is activated following CNS injury. ILC2s are present throughout the naïve mouse meninges, though are concentrated around the dural sinuses, and have a unique transcriptional profile relative to lung ILC2s. After spinal cord injury, meningeal ILC2s are activated in an IL-33 dependent manner, producing type 2 cytokines. Using RNAseq, we characterized the gene programs that underlie the ILC2 activation state. Finally, addition of wild type lung-derived ILC2s into the meningeal space of IL-33R-/- animals improves recovery following spinal cord injury. These data characterize ILC2s as a novel meningeal cell type that responds to and functionally affects outcome after spinal cord injury, and could lead to new therapeutic insights for CNS injury or other neuroinflammatory conditions.

2016-12-13 | GSE90908 | GEO

Murine embryonic stem cells synthesize retinoic acid to promote their own spontaneous differentiation

Project description:Embryonic stem cells (ESC) are derived from blastocyst-stage embryos and are thought to be functionally equivalent to the inner cell mass in their developmental potential. ESCs pluripotency is maintained through a complex interplay of different signaling pathways and a network of transcription factors, which is centered around Oct3/4, Sox2 and Nanog. Although, in general, much is known about this pluripotency self-renewal circuitry, the molecular events that lead ESC to exit from pluripotency and begin differentiation are currently less known. Retinoic acid, an active metabolite of the vitamin A (retinol), plays important and pleiotropic roles in vertebrate embryonic development and ESC differentiation. Here we demonstrate that RA promotes early steps of ESC differentiation, and that ESC increase their capacity to synthesize RA during spontaneous differentiation as embryoid bodies, up-regulating the RA biosynthetic pathway components RDH1, RDH10, ADH3, RALDH2, and CRABP2. Microarray derived from total RNA of mESC not treated or treated with all-trans retinoic acid (ATRA) for 2 hours.

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