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

Abstract

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-DNAbinding 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.N eural crest cells (NCCs) originate from the neural crest of the dorsal neural tube and migrate to many regions of the embryo, where they differentiate into a variety of local cells, including cardiovascular tissues (1). NCCs that emigrate from the neural crest of rhombomere 6-8 to pharyngeal arches and the heart are essential for the patterning of pharyngeal arch arteries (PAAs) and the cardiac outflow tract (OFT) (2, 3). These NCCs also differentiate into vascular smooth muscle cells (SMCs) of PAAs and the muscular septum of the aorta and pulmonary trunk (4, 5). In contrast, NCCs from the cephalic neural tube migrate to the face and forebrain to form craniofacial bones, as well as SMCs of facial and forebrain vessels (6). Thus, NCCs are critical for the formation of cardiac OFT and vascular supplies of large areas of the body.Disruption of NCC development, either directly or indirectly, results in many forms of human birth defects with cardiovascular malformations, including Alagille, Carpenter, Ivemark, Leopard, Williams, DiGeorge, and CHARGE syndromes (7). These syndromes involve defects in PAAs or cardiac OFT, such as coarctation of the aorta, interrupted aortic arch, pulmonary artery stenosis, double-outlet right ventricle, tetralogy of Fallot, or persistent truncus arteriosus. During PAA and OFT development, NCCs are regulated by numerous transcription factors, including Pax3, Pbx1/2/3, Tbx1/2/3/20, Msx1/2, Hand2, AP2a, Cited2, Pitx2, Sox4, Foxc1/c2/d3/h1, Fog2, Gata3/4/6, and Notch/NICD (8). Such extensive involvement of transcription factors indicates the importance of gene pr...

97 BRG1 Plays an Essential Role in Development and Homeostasis of the Duodenum Through Regulation of Notch Signaling

“…In addition, inactivating mutations in Brg1 and other subunits of SWI/SNF complexes have been identified in various human cancers, including the pancreas and intestine (Helming et al, 2014;Wilson and Roberts, 2011). Furthermore, Brg1 is involved in cell proliferation during embryonic development (Hang et al, 2010;Seo et al, 2005;Li et al, 2013), a period in which Brg1 depletion increases the number of proliferative cells in neural plate (Seo et al, 2005). In line with these data, we found that the number of proliferative cells was elevated in Brg1-deficient duodenum.…”

“…Brg1 is required for inhibition of apoptosis in the development of various cell types and organs, including neurons (Li et al, 2013), smooth muscle (Zhang et al, 2011) and blood cells (Griffin et al, 2008); consequently, knockout of Brg1 increases the rate of apoptosis in these tissues. Our data showing that elevated apoptosis was reversed by Notch1 ICD overexpression in VBN mice demonstrate that marked downregulation of Notch signaling is responsible for increased apoptosis in Brg1-deficient duodenum.…”

“…Brg1 is involved in apoptosis and cell proliferation during organ development (Griffin et al, 2008;Hang et al, 2010;Li et al, 2013;Seo et al, 2005;Zhang et al, 2011). Therefore, we next investigated whether the abnormal villous structure in Brg1-deficient duodenum was associated with changes in apoptosis or cell proliferation.…”

“…Brg1-null mice die during the peri-implantation stage, whereas Brm-null mice develop normally (Bultman et al, 2000;Reyes et al, 1998). Recent studies showed that Brg1 is essential for development or homeostasis of various organs and cell types, including heart (Hang et al, 2010;Takeuchi et al, 2011), vasculature (Davis et al, 2013;Griffin et al, 2008Griffin et al, , 2011, ureter (Weiss et al, 2013), smooth muscle (Zhang et al, 2011) and neurons (Li et al, 2013;Matsumoto et al, 2006;Seo et al, 2005). In the intestine, Brg1 is essential for maintenance of intestinal stem cells (Holik et al, 2013).…”

Snail2/Slug cooperates with Polycomb repressive complex 2 (PRC2) to regulate neural crest development

“…For example, it has been shown that the histone H3K9me3/H3K36me3 demethylase JmjD2A regulates neural crest specification in the chick (StroblMazzulla et al, 2010), and the PRC1 component Ring1b specifically modulates craniofacial chondrocyte differentiation in zebrafish without affecting early induction and migration of the neural crest (van der Velden et al, 2013). Several components of chromatin remodeling complexes, such as Brg1 and CHD7, have also been reported to influence neural crest induction and/or differentiation (Eroglu et al, 2006;Bajpai et al, 2010;Weider et al, 2012;Li et al, 2013). Furthermore, both microRNA-processing enzymes and several specific microRNAs have been shown to regulate neural crest migration or affect neural crest-derived tissues, such as cranial and cardiovascular structures (Prasad et al, 2012;Strobl-Mazzulla et al, 2012;Mayanil, 2013).…”