Brg1 governs distinct pathways to direct multiple aspects of mammalian neural crest cell development

Division of Cardiovascular Medicine, Department of Medicine, Department of Chemical and Systems Biology, and Division of Pediatric Cardiology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2013; 110(5). DOI: 10.1073/pnas.1218072110
Source: PubMed


Development of the cerebral vessels, pharyngeal arch arteries (PAAs). and cardiac outflow tract (OFT) requires multipotent neural crest cells (NCCs) that migrate from the neural tube to target tissue destinations. Little is known about how mammalian NCC development is orchestrated by gene programming at the chromatin level, however. Here we show that Brahma-related gene 1 (Brg1), an ATPase subunit of the Brg1/Brahma-associated factor (BAF) chromatin-remodeling complex, is required in NCCs to direct cardiovascular development. Mouse embryos lacking Brg1 in NCCs display immature cerebral vessels, aberrant PAA patterning, and shortened OFT. Brg1 suppresses an apoptosis factor, Apoptosis signal-regulating kinase 1 (Ask1), and a cell cycle inhibitor, p21(cip1), to inhibit apoptosis and promote proliferation of NCCs, thereby maintaining a multipotent cell reservoir at the neural crest. Brg1 also supports Myosin heavy chain 11 (Myh11) expression to allow NCCs to develop into mature vascular smooth muscle cells of cerebral vessels. Within NCCs, Brg1 partners with chromatin remodeler Chromodomain-helicase-DNA-binding protein 7 (Chd7) on the PlexinA2 promoter to activate PlexinA2, which encodes a receptor for semaphorin to guide NCCs into the OFT. Our findings reveal an important role for Brg1 and its downstream pathways in the survival, differentiation, and migration of the multipotent NCCs critical for mammalian cardiovascular development.

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    • "Patients with hereditary cerebral amyloidosis were found to develop severe CAA, along with hemorrhagic strokes and vascular dementia due to SMC degeneration (Fossati et al., 2010). On the other hand, the differences in apolipoprotein E (APOE) genotypes seem to have notable effect on the course of sporadic CAA as SMCs can internalize Ab via the lipoprotein pathway involving APOE (Ruzali et al., 2013). Carrier of APOE4 showed increased incidence of Ab accumulation, rendering the vessel walls more prone to vasculopathic rupture (Strittmatter et al., 1993; Schmechel et al., 1993; Mazur-Kolecka et al., 2003). "
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    • "In brief, rat GAP-43 promoter, which spans (− 935 to + 55), was cloned into the XhoI–HindIII sites of pREP4-Luc reporter plasmids (Li et al., 2013; Liu et al., 2001). The construct was then transfected into Neuro2a cells with FuGENE HD reagent (Roche) along with pREP7- RLuc as a transfection efficiency control, BRG1 and Nls-srGAP3 ΔF-BAR expression vector with the appropriate empty vector control. "
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