Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease

Abstract

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...

Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish

“…The expression pattern of fluorescent proteins in these reporter lines was similar to the previously reported expression pattern of pdgfrb mRNA (Wang et al, 2014;French et al, 2014;Wiens et al, 2010). In the TgBAC ( pdgfrb:EGFP) embryos, EGFP started to be expressed around the 8-somite stage in the cranial neural crests in which pdgfrb mRNA is expressed (French et al, 2014) (Fig. S1A,B; Movies 1 and 2).…”

“…MCs play an essential role in vascular stability and homeostasis (Armulik et al, 2011). Therefore, loss or detachment of MCs leads to various vascular diseases (French et al, 2014;Garg et al, 2014;Joutel et al, 1996).…”

Differential Effect of White-Matter Lesions and Covert Brain Infarcts on the Risk of Ischemic Stroke and Intracerebral Hemorrhage

“…Atrial fibrillation, the main cause of cardioembolic IS, may partly mediate this association; although mechanisms linking atrial fibrillation to PWMHV are unclear, they may include thromboemboli, chronic cerebral hypoperfusion in case of chronically altered cerebral perfusion, caused by beat-to-beat variation in stroke volume, 12 and possibly shared risk factors, including genetic. 13 PWM BI indicates brain infarct; CI, confidence interval; ext-WMHV, extensive total white-matter hyperintensity volume; HR, hazard ratio; ICH, intracerebral hemorrhage; and WMHV, white-matter hyperintensity volume.…”

Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation

“…Recent studies have shown that FOXC2 regulates connexin 37 (CX37) and calcineurin/NFAT signaling during lymphatic valve formation (20)(21)(22), as well as lymphatic endothelial cell quiescence (23). Both FOXC1 and FOXC2 play a role in the development of the mouse and human eye (24)(25)(26)(27)(28), and mutations or changes in the copy number of human FOXC1 are associated with autosomal-dominant Axenfeld-Rieger syndrome (ARS), which is characterized by anterior eye segment defects, glaucoma, and cerebral small vessel disease (29,30). However, the role of FOXC1 in the lymphatic system has yet to be explored, and it remains to be elucidated how FOXC1 and FOXC2 function in early lymphatic vessel formation.…”