Abstract
Connection of the heart to the systemic circulation is a critical developmental event that requires selective preservation of embryonic vessels (aortic arches). However, why some aortic arches regress while others are incorporated into the mature aortic tree remains unclear. By microdissection and deep sequencing in mouse, we find that neural crest (NC) only differentiates into vascular smooth muscle cells (SMCs) around those aortic arches destined for survival and reorganization, and identify the transcription factor Gata6 as a crucial regulator of this process. Gata6 is expressed in SMCs and its target genes activation control SMC differentiation. Furthermore, Gata6 is sufficient to promote SMCs differentiation in vivo, and drive preservation of aortic arches that ought to regress. These findings identify Gata6-directed differentiation of NC to SMCs as an essential mechanism that specifies the aortic tree, and provide a new framework for how mutations in GATA6 lead to congenital heart disorders in humans.
Highlights
In mammals, effective delivery of oxygenated blood from the heart to the systemic circulation relies on physical separation from deoxygenated blood in the pulmonary circulation
We found that a considerable proportion of genes contained in the gene ontology (GO) ‘heart development’ is associated with aortic arches (AAs) and/or outflow tract (OFT) phenotypes (36%; 12 out of 33)
Myocd encodes for a transcription factor (TF) that is sufficient to activate the program of smooth muscle cells (SMCs) differentiation (Li et al, 2003; Wang et al, 2003) and functions in complex with the MADS box TF serum response factor (SRF)
Summary
Effective delivery of oxygenated blood from the heart to the systemic circulation relies on physical separation from deoxygenated blood in the pulmonary circulation This separation is contingent upon two critical developmental events: cardiac septation, including division of the outflow tract (OFT) into the ascending aorta and the pulmonary trunk (Hutson and Kirby, 2007; Kirby and Hutson, 2010); and complex remodeling of the embryonic circulation. Failure to separate pulmonary and systemic circulations in this manner results in congenital heart disease characterized by cyanosis, due to the mixing of deoxygenated with oxygenated blood (Hutson and Kirby, 2007; Keyte and Hutson, 2012) This need for separation and the consequences of cyanosis have made understanding the mechanism(s) of OFT septation and AA remodeling a high priority. In addition to haemodynamics (Yashiro et al, 2007), cardiac neural crest (NC) cells, a subpopulation of the cranial NC, are known
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