title: Notch3 establishes brain vascular integrity by regulating pericyte number.
abstract: Brain pericytes are important regulators of brain vascular integrity, permeability and blood flow. Deficiencies of brain pericytes are associated with neonatal intracranial hemorrhage in human fetuses, as well as stroke and neurodegeneration in adults. Despite the important functions of brain pericytes, the mechanisms underlying their development are not well understood and little is known about how pericyte density is regulated across the brain. The Notch signaling pathway has been implicated in pericyte development, but its exact roles remain ill defined. Here, we report an investigation of the Notch3 receptor using zebrafish as a model system. We show that zebrafish brain pericytes express notch3 and that notch3 mutant zebrafish have a deficit of brain pericytes and impaired blood-brain barrier function. Conditional loss- and gain-of-function experiments provide evidence that Notch3 signaling positively regulates brain pericyte proliferation. These findings establish a new role for Notch signaling in brain vascular development whereby Notch3 signaling promotes expansion of the brain pericyte population.
authors.affiliation: Departments of Pediatrics and Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Wang
authors.forename: Luyuan
authors.initials: L
authors.lastname: Pan
authors.forename: Cecilia B
authors.initials: CB
authors.lastname: Moens
authors.forename: Bruce
authors.initials: B
authors.lastname: Appel
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001812:Blood-Brain Barrier / Q000254:growth & development / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000254:growth & development* / Q000378:metabolism*; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D009154:Mutation; D020286:Pericytes / Q000166:cytology* / Q000378:metabolism*; D000071656:Receptor, Notch3; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C520425:Notch3 protein, zebrafish; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D029961:Zebrafish Proteins; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: Blood-brain barrier; Intraventricular hemorrhage; Notch3; Pericytes; Vasculature