Radial Glial Neural Progenitors Regulate Nascent Brain Vascular Network Stabilization Via Inhibition of Wnt Signaling

Ma, Shang; Kwon, Hyo Jun; Johng, Heidi; Zang, Keling; Huang, Zhen

doi:10.1371/journal.pbio.1001469

Cited by 91 publications

(96 citation statements)

References 71 publications

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“…1C,D). A detailed analysis of the hypoxic level in fetal Hif1a CKO mouse brains revealed abundant hypoxic tissue in all forebrain areas but particularly where the vessels starts to sprout and invade into the cortical plate (Ma et al, 2013). Hif1α regulates angiogenesis during embryonic brain development (Hashimoto and Shibasaki, 2015) and, indeed, angiogenesis was disrupted in the knockout mice and thus a normal oxygen supply could not be ensured (Fig.…”

Section: Resultsmentioning

confidence: 99%

Brain oxygen tension controls the expansion of outer subventricular zone-like basal progenitors in the developing mouse brain

et al. 2015

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The mammalian neocortex shows a conserved six-layered structure that differs between species in the total number of cortical neurons produced owing to differences in the relative abundance of distinct progenitor populations. Recent studies have identified a new class of proliferative neurogenic cells in the outer subventricular zone (OSVZ) in gyrencephalic species such as primates and ferrets. Lissencephalic brains of mice possess fewer OSVZ-like progenitor cells and these do not constitute a distinct layer. Most in vitro and in vivo studies have shown that oxygen regulates the maintenance, proliferation and differentiation of neural progenitor cells. Here we dissect the effects of fetal brain oxygen tension on neural progenitor cell activity using a novel mouse model that allows oxygen tension to be controlled within the hypoxic microenvironment in the neurogenic niche of the fetal brain in vivo. Indeed, maternal oxygen treatment of 10%, 21% and 75% atmospheric oxygen tension for 48 h translates into robust changes in fetal brain oxygenation. Increased oxygen tension in fetal mouse forebrain in vivo leads to a marked expansion of a distinct proliferative cell population, basal to the SVZ. These cells constitute a novel neurogenic cell layer, similar to the OSVZ, and contribute to corticogenesis by heading for deeper cortical layers as a part of the cortical plate.

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Section: Resultsmentioning

confidence: 99%

Brain oxygen tension controls the expansion of outer subventricular zone-like basal progenitors in the developing mouse brain

et al. 2015

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“…For example, macrophage-derived Wnt5a interferes with retinal vessel formation and, similarly, glia cells inhibit canonical Wnt signaling in ECs and subsequent vessel regression (Stefater et al, 2011;Ma et al, 2013). We analyzed in the present study the contribution of EC-derived Wnt ligands in controlling vessel remodeling.…”

Section: Discussionmentioning

confidence: 98%

Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis

Korn

Scholz

et al. 2014

Journal of Cell Science

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Multiple cell types involved in the regulation of angiogenesis express Wnt ligands. Although β-catenin dependent and independent Wnt signaling pathways have been shown to control angiogenesis, the contribution of individual cell types to activate these downstream pathways in endothelial cells (ECs) during blood vessel formation is still elusive. To investigate the role of ECs in contributing Wnt ligands for regulation of blood vessel formation, we conditionally deleted the Wnt secretion factor Evi in mouse ECs (Evi-ECKO). Evi-ECKO mice showed decreased microvessel density during physiological and pathological angiogenesis in the postnatal retina and in tumors, respectively. The reduced microvessel density resulted from increased vessel regression accompanied by decreased EC survival and proliferation. Concomitantly, survival-related genes were downregulated and cell cycle arrest-and apoptosis-inducing genes were upregulated. EVI silencing in cultured HUVECs showed similar target gene regulation, supporting a mechanism of EC-derived Wnt ligands in controlling EC function. ECs preferentially expressed non-canonical Wnt ligands and canonical target gene expression was unaffected in Evi-ECKO mice. Furthermore, the reduced vascularization of Matrigel plugs in Evi-ECKO mice could be rescued by introduction of non-canonical Wnt5a. Treatment of mouse pups with the non-canonical Wnt inhibitor TNP470 resulted in increased vessel regression accompanied by decreased EC proliferation, thus mimicking the proliferation-dependent Evi-ECKO remodeling phenotype. Taken together, this study identified EC-derived non-canonical Wnt ligands as regulators of EC survival, proliferation and subsequent vascular pruning during developmental and pathological angiogenesis.

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“…The association of neuronal processes with cerebral vasculature is also important for the development and maintenance of the BBB. During development, vascular endothelial growth factor (VEGF) signaling appears to drive vascular patterning (29); however, neural progenitor cells contribute to the stabilization of the nascent network (30). Post-developmentally, it is likely that neuronal activity continues to participate in the maintenance of the vascular network (31), with astrocytes, rather than neurons, as the chief mediators of cerebrovascular permeability.…”

Section: Neuronsmentioning

confidence: 99%

The Translational Significance of the Neurovascular Unit

McConnell

Kersch

Woltjer

et al. 2017

Journal of Biological Chemistry

247

194

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Edited by Paul E. FraserThe mammalian brain is supplied with blood by specialized vasculature that is structurally and functionally distinct from that of the periphery. A defining feature of this vasculature is a physical blood-brain barrier (BBB). The BBB separates blood components from the brain microenvironment, regulating the entry and exit of ions, nutrients, macromolecules, and energy metabolites. Over the last two decades, physiological studies of cerebral blood flow dynamics have demonstrated that substantial intercellular communication occurs between cells of the vasculature and the neurons and glia that abut the vasculature. These findings suggest that the BBB does not function independently, but as a module within the greater context of a multicellular neurovascular unit (NVU) that includes neurons, astrocytes, pericytes, and microglia as well as the blood vessels themselves. Here, we describe the roles of these NVU components as well as how they act in concert to modify cerebrovascular function and permeability in health and in select diseases.

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Radial Glial Neural Progenitors Regulate Nascent Brain Vascular Network Stabilization Via Inhibition of Wnt Signaling

Abstract: Radial glial cells, which are neural stem cells well known for their role in neurogenesis, also play an unexpected role in stabilizing nascent blood vessels in the brain.

Cited by 91 publications

References 71 publications

Brain oxygen tension controls the expansion of outer subventricular zone-like basal progenitors in the developing mouse brain

Brain oxygen tension controls the expansion of outer subventricular zone-like basal progenitors in the developing mouse brain

Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis

The Translational Significance of the Neurovascular Unit

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