β1-Integrin Alters Ependymal Stem Cell BMP Receptor Localization and Attenuates Astrogliosis after Spinal Cord Injury

North, Hilary A.; Pan, Liuliu; McGuire, Tammy L.; Brooker, Sarah M.; Kessler, John A.

doi:10.1523/jneurosci.4546-14.2015

Cited by 42 publications

(36 citation statements)

References 50 publications

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“…Interestingly, it has been reported that β1-integrins can suppress BMP signaling by sequestering BMP receptors away from the lipid raft environment, while deletion of β1-integrins from ependymal cells of the spinal cord leads to inappropriate activation of BMP signaling (North et al, 2015), similar to the situation we report here in in β1LE lenses, suggesting a possible molecular mechanism for our observations.…”

Section: Discussionsupporting

confidence: 87%

β1‐integrin controls cell fate specification in early lens development

et al. 2016

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Integrins are heterodimeric cell surface molecules that mediate cell-extracellular matrix (ECM) adhesion, ECM assembly, and regulation of both ECM and growth factor induced signaling. However, the developmental context of these diverse functions is not clear. Loss of β1-integrin from the lens vesicle (mouse E10.5) results in abnormal exit of anterior lens epithelial cells (LECs) from the cell cycle and their aberrant elongation toward the presumptive cornea by E12.5. These cells lose expression of LEC markers and initiate expression of the Maf (also known as c-Maf) and Prox1 transcription factors as well as other lens fiber cell markers, β1-integrin null LECs also upregulate the ERK, AKT and Smad1/5/8 phosphorylation indicative of BMP and FGF signaling. By E14.5, β1-integrin null lenses have undergone a complete conversion of all lens epithelial cells into fiber cells. These data suggest that shortly after lens vesicle closure, β1-integrin blocks inappropriate differentiation of the lens epithelium into fibers, potentially by inhibiting BMP and/or FGF receptor activation. Thus, β1-integrin has an important role in fine-tuning the response of the early lens to the gradient of growth factors that regulate lens fiber cell differentiation.

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Section: Discussionsupporting

confidence: 87%

β1‐integrin controls cell fate specification in early lens development

et al. 2016

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“…Our findings indicate that β1‐integrin helps to maintain radial NSCs in the SGZ and inhibits astrocytic differentiation of these cells. Ablation of β1‐integrin from ependymal zone stem cells also increases astrogliogenesis following spinal cord injury (North et al, ), consistent with a role for β1‐integrin in restricting astrocytic differentiation. Furthermore, genetic deletion of β1‐integrin in astrocytes during development leads to a partial reactive gliosis phenotype in the early postnatal and adult central nervous system, characterized by upregulation of GFAP expression and astrocytic hypertrophy in the brain and spinal cord (Robel et al, ).…”

Section: Discussionmentioning

confidence: 68%

β1‐integrin restricts astrocytic differentiation of adult hippocampal neural stem cells

Brooker

Bond

Peng

et al. 2016

Glia

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Integrins are transmembrane receptors that mediate cell-extracellular matrix and cell-cell interactions. The β1-integrin subunit is highly expressed by embryonic neural stem cells (NSCs) and is critical for NSC maintenance in the developing nervous system, but its role in the adult hippocampal niche remains unexplored. We show that β1-integrin expression in the adult mouse dentate gyrus (DG) is localized to radial NSCs and early progenitors, but is lost in more mature progeny. Although NSCs in the hippocampal subgranular zone (SGZ) normally only infrequently differentiate into astrocytes, deletion of β1-integrin significantly enhanced astrocyte differentiation. Ablation of β1-integrin also led to reduced neurogenesis as well as depletion of the radial NSC population. Activation of integrin-linked kinase (ILK) in cultured adult NSCs from β1-integrin knockout mice reduced astrocyte differentiation, suggesting that at least some of the inhibitory effects of β1-integrin on astrocytic differentiation are mediated through ILK. In addition, β1-integrin conditional knockout also resulted in extensive cellular disorganization of the SGZ as well as non-neurogenic regions of the DG. The effects of β1-integrin ablation on DG structure and astrogliogenesis show sex-specific differences, with the effects following a substantially slower time-course in males. β1-integrin thus plays a dual role in maintaining the adult hippocampal NSC population by supporting the structural integrity of the NSC niche and by inhibiting astrocytic lineage commitment. GLIA 2016;64:1235-1251.

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“…In the HAP1 human cell line, ACVR1 CRISPR/Cas9 knockout suppressed fibrinogen-induced Id1 (Figure S3D). Lipid rafts regulate BMP receptor signaling and progenitor cell differentiation (North et al, 2015). Pre-treating OPCs with the lipid raft disrupting methyl-β-cyclodextrin reduced fibrinogen-induced phospho-Smad1/5 levels by ∼45% (Figure S3E), suggesting fibrinogen enhances ACVR1 receptor association in lipid rafts to activate BMP signaling.…”

Section: Resultsmentioning

confidence: 99%

Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage

Petersen

Ryu

Chang

et al. 2017

Neuron

140

145

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Summary Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs), while promoting an astrocytic fate in vitro. Fibrinogen effects are rescued by BMP type I receptor inhibition using dorsomorphin homologue 1 (DMH1) or CRISPR/Cas9 activin A receptor type I (ACVR1) knockout in OPCs. Fibrinogen and the BMP target Id2 are increased in demyelinated multiple sclerosis (MS) lesions. Therapeutic depletion of fibrinogen decreases BMP signaling and enhances remyelination in vivo. Targeting fibrinogen may be an upstream therapeutic strategy to promote the regenerative potential of CNS progenitors in diseases with remyelination failure.

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β1-Integrin Alters Ependymal Stem Cell BMP Receptor Localization and Attenuates Astrogliosis after Spinal Cord Injury

Cited by 42 publications

References 50 publications

β1‐integrin controls cell fate specification in early lens development

β1‐integrin controls cell fate specification in early lens development

β1‐integrin restricts astrocytic differentiation of adult hippocampal neural stem cells

Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage

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