Foxc1 is required by pericytes during fetal brain angiogenesis

Siegenthaler, Julie A.; Choe, Youngshik; Patterson, Katelin P.; Hsieh, Ivy; Li, Dan; Jaminet, Shou Ching; Daneman, Richard; Kume, Tsutomu; Huang, Eric J.; Pleasure, Samuel J.

doi:10.1242/bio.20135009

Cited by 67 publications

(73 citation statements)

References 61 publications

(99 reference statements)

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“…Eighteen patients with either a FOXC1 mutation or copy number variation (CNV) (comprising missense sive involvement of Foxc1 in vascular development (14)(15)(16). The latter encompasses essential roles in arterial specification, angiogenesis regulation, endothelial lymphatic cell sprouting (17), as well as a requirement for Foxc1 in brain pericytes (18). Here, we demonstrate a role for FOXC1 in cerebrovascular disease through targeted genome-wide association (GWA) analysis, MRI of glaucoma patients with FOXC1-attributable Axenfeld-Rieger syndrome (ARS), and detailed zebrafish analyses.…”

Section: Mutation Of Foxc1 and Pitx2 Induces Cerebral Small-vessel DImentioning

confidence: 78%

Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease

French¹,

Seshadri²,

DeStefano³

et al. 2014

J. Clin. Invest.

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B r i e f r e p o r t4 IntroductionStroke is a leading cause of morbidity and mortality, whose prevalence increases dramatically with age. Despite its substantial heritable basis, only a small number of causative genes have so far been identified, generally for severe early-onset phenotypes (cerebral autosomal dominant or recessive arteriopathy with subcortical infarcts and leukoencephalopathy: CADASIL [NOTCH3], CARASIL [HTRA1], and porencephaly [COL4A1]) (1-3). Such cases have revealed important pathways that contribute to stroke, including the roles of Notch and TGF-β signaling.In the same way, the vascular basement membrane's contribution (COL4A1 and COL4A2) (3, 4) to juvenile stroke phenotypes further stimulated investigation of the cellular components (endothelial and mural cells) upon which brain vascular integrity depends. The demonstration that Notch signaling regulates pericyte numbers (5, 6) has in turn provided a mechanistic explanation for disorders such as CADASIL. These examples of juvenile stroke resulting from severe alterations in brain vascular development raise the intriguing possibility that milder changes contribute to late-onset disease and that a larger proportion of strokes have embryonic origins. It is therefore notable that the same genes regulate cerebral structural development and angiogenesis (7) and that the cell populations essential for cerebral vascular homeostasis (pericytes and vascular smooth muscle) are predominantly derived from the neural crest (8, 9). The increasing prevalence of stroke exerts disproportionately severe effects on the quality of life of affected individuals and their families. Consequently, phenotypes predictive of future stroke merit investigation, with the goal of developing treatments targeting causative pathways and preventing a frequently preterminal disease. One such phenotype is cerebral small-vessel disease (CSVD), which represents a major risk factor for both ischemic and hemorrhagic stroke (10-13). Characterized by perturbed perforating end-artery function, CSVD results in lesions apparent on MRI that encompass white matter hyperintensities (WMHs), dilated perivascular spaces, microbleeds, and lacunar infarcts. These markers of cerebrovascular pathology provide opportunities for gene discovery and for defining the mechanisms that contribute to subsequent stroke.Our study evaluated the hypothesis that the forkhead box transcription factor FOXC1, which patterns multiple organs including the CNS, contributes to CSVD. It was prompted by a higher incidence of self-reported stroke in some of our local pedigrees with FOXC1 mutations and supported experimentally by: (a) blood-stained hydrocephalus in murine Foxc1 -/-mutants, (b) related zebrafish foxc1 morphant phenotypes, and (c) the extenPatients with cerebral small-vessel disease (CSVD) exhibit perturbed end-artery function and have an increased risk for stroke and age-related cognitive decline. Here, we used targeted genome-wide association (GWA) analysis and defined a CSVD locus adjacent to the forkh...

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Section: Mutation Of Foxc1 and Pitx2 Induces Cerebral Small-vessel DImentioning

confidence: 78%

Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease

French¹,

Seshadri²,

DeStefano³

et al. 2014

J. Clin. Invest.

Self Cite

123

124

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“…Cell density was determined by averaging the number of Erg + endothelial nuclei or Zic1 + pericyte nuclei per 40× image (230 μm×230 μm) field in at least four distinct fields as previously described (Siegenthaler et al, 2013). Pericyte:endothelial cell ratio (PC:EC) was calculated by dividing the average pericyte density by the average endothelial cell density.…”

Section: Cell Density and Proliferationmentioning

confidence: 99%

Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain

et al. 2014

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Vascular development of the central nervous system and blood-brain barrier (BBB) induction are closely linked processes. The role of factors that promote endothelial sprouting and vascular leak, such as vascular endothelial growth factor A, are well described, but the factors that suppress angiogenic sprouting and their impact on the BBB are poorly understood. Here, we show that integrin αVβ8 activates angiosuppressive TGFβ gradients in the brain, which inhibit endothelial cell sprouting. Loss of αVβ8 in the brain or downstream TGFβ1-TGFBR2-ALK5-Smad3 signaling in endothelial cells increases vascular sprouting, branching and proliferation, leading to vascular dysplasia and hemorrhage. Importantly, BBB function in Itgb8 mutants is intact during early stages of vascular dysgenesis before hemorrhage. By contrast, Pdgfb ret/ret mice, which exhibit severe BBB disruption and vascular leak due to pericyte deficiency, have comparatively normal vascular morphogenesis and do not exhibit brain hemorrhage. Our data therefore suggest that abnormal vascular sprouting and patterning, not BBB dysfunction, underlie developmental cerebral hemorrhage.

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“…The Pdgfrb‐Cre line (Foo et al ., 2006), where Cre recombinase expression is driven by a transgenic fragment of the gene for platelet‐derived growth factor receptor β ( Pdgfrb ), has been used extensively to specifically target mural cells, namely vascular smooth muscle cells, pericytes and hepatic stellate cells; examples are given in ref (Abraham et al ., 2008; Foo et al ., 2006; Greif et al ., 2012; Henderson et al ., 2013; Jeansson et al ., 2011; Kogata et al ., 2009; Siegenthaler et al ., 2013; Stenzel et al ., 2009; Ye et al ., 2009; You et al ., 2014). We (Stanczuk et al ., 2015) and others (Klotz et al ., 2015) recently showed that Pdgfrb‐Cre unexpectedly also targets a large proportion of embryonic lymphatic endothelial cells (LECs) in the developing mesentery (Stanczuk et al ., 2015) and the heart (Klotz et al ., 2015).…”

Section: Introductionmentioning

confidence: 99%

Pdgfrb‐Cre targets lymphatic endothelial cells of both venous and non‐venous origins

Ulvmar

Martínez-Corral

Stanczuk

et al. 2016

Genesis

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The Pdgfrb‐Cre line has been used as a tool to specifically target pericytes and vascular smooth muscle cells. Recent studies showed additional targeting of cardiac and mesenteric lymphatic endothelial cells (LECs) by the Pdgfrb‐Cre transgene. In the heart, this was suggested to provide evidence for a previously unknown nonvenous source of LECs originating from yolk sac (YS) hemogenic endothelium (HemEC). Here we show that Pdgfrb‐Cre does not, however, target YS HemEC or YS‐derived erythro‐myeloid progenitors (EMPs). Instead, a high proportion of ECs in embryonic blood vessels of multiple organs, as well as venous‐derived LECs were targeted. Assessment of temporal Cre activity using the R26‐mTmG double reporter suggested recent occurrence of Pdgfrb‐Cre recombination in both blood and lymphatic ECs. It thus cannot be excluded that Pdgfrb‐Cre mediated targeting of LECs is due to de novo expression of the Pdgfrb‐Cre transgene or their previously established venous endothelial origin. Importantly, Pdgfrb‐Cre targeting of LECs does not provide evidence for YS HemEC origin of the lymphatic vasculature. Our results highlight the need for careful interpretation of lineage tracing using constitutive Cre lines that cannot discriminate active from historical expression. The early vascular targeting by the Pdgfrb‐Cre also warrants consideration for its use in studies of mural cells. genesis 54:350–358, 2016. © 2016 The Authors. Genesis Published by Wiley Periodicals, Inc.

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Foxc1 is required by pericytes during fetal brain angiogenesis

Cited by 67 publications

References 61 publications

Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease

Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease

Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain

Pdgfrb‐Cre targets lymphatic endothelial cells of both venous and non‐venous origins

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