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.
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.
"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). "
[Show abstract][Hide abstract] ABSTRACT: There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Aβ) accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we leverage human pluripotent stem cells to generate vascular smooth muscle cells (SMCs) from neural crest progenitors, recapitulating brain-vasculature-specific attributes of Aβ metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate Aβ uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to Aβ clearance by suppressing LRP1 expression. This enabled us to develop an assay of Aβ uptake by using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high-throughput format, demonstrating the value of stem-cell-based phenotypic screening for novel therapeutics and drug repurposing, aimed at alleviating amyloid burden.
"On the other hand, any selective cell death was not found in these treatments. In mouse neural crest cells, it has been shown that BRG1, the catalytic subunit of SWI/ SNF-B, suppresses the apoptosis and promotes the proliferation (Li et al., 2013). Thus, the maintenance of the undifferentiated state of the trunk neural crest cells may be due to the promotion of the proliferation of the undifferentiated neural crest cells by BMP/Wnt signaling and the chromatin remodelers. "
[Show abstract][Hide abstract] ABSTRACT: We analyzed roles of two chromatin remodelers, Chromodomain Helicase DNA-binding protein 7 (CHD7) and SWItch/Sucrose NonFermentable-B (SWI/SNF-B), and Bone Morphogenetic Protein (BMP)/Wnt signaling in the maintenance of the multipotency of mouse trunk neural crest cells, leading to the formation of mouse neural crest-derived stem cells (mouse NCSCs). CHD7 was expressed in the undifferentiated neural crest cells and in the dorsal root ganglia (DRG) and sciatic nerve, typical tissues containing NCSCs. BMP/Wnt signaling stimulated the expression of CHD7 and participated in maintaining the multipotency of neural crest cells. Furthermore, the promotion of CHD7 expression maintained the multipotency of these cells. The inhibition of CHD7 and SWI/SNF-B expression significantly suppressed the maintenance of the multipotency of these cells. In addition, BMP/Wnt treatment promoted CHD7 expression and caused the increase of the percentage of multipotent cells in DRG. Thus, the present data suggest that the chromatin remodelers as well as BMP/Wnt signaling play essential roles in the maintenance of the multipotency of mouse trunk neural crest cells and in the formation of mouse NCSCs.
Mechanisms of Development 05/2014; 133. DOI:10.1016/j.mod.2014.05.001 · 2.44 Impact Factor
"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. "
[Show abstract][Hide abstract] ABSTRACT: The Slit-Robo GTPase activating protein 3 (srGAP3) is an important modulator of actin cytoskeletal dynamics and has an important influence on a variety of neurodevelopmental processes. Mutations in the SRGAP3 gene on chromosome 3p25 have been found in patients with intellectual disability. Genome-wide association studies and behavioral assays of knockout mice had also revealed SRGAP3 as a risk gene for schizophrenia. We have recently shown that srGAP3 protein undergoes regulated shuttling between the cytoplasm and the nucleus during neuronal development. It is shown here that nuclear-localized srGAP3 interacts with the SWI/SNF remodeling factor Brg1. This interaction is mediated by the C-terminal of srGAP3 and the ATPase motif of Brg1. In the primary cultured rat cortical neurons, the levels of nuclear-localized srGAP3 and its interaction with Brg1 have a significant impact on dendrite complexity. Furthermore, the interaction between srGAP3 and Brg1 was also involved in valporic acid (VPA) -induced neuronal differentiation of Neuro2a cells. We then show that GTP-bound Rac1 and GAP-43 may be potential mediators of nuclear srGAP3 and Brg1. Our results not only indicate a novel signaling pathway that contributes to neuronal differentiation and dendrite morphology, but also implicate a novel molecular mechanism underlying srGAP3 regulation of gene expression.
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