Combinatorial transcriptional interaction within the cardiac neural crest: A pair of HANDs in heart formation

Abstract

The cardiac neural crest migrate from rostral dorsal neural folds and populate the branchial arches, which directly contribute to cardiac-outflow structures. Although neural crest cell specification is associated with a number of morphogenic factors, little is understood about the mechanisms by which transcription factors actually implement the transcriptional programs that dictate cell migration and later the differentiation into the proper cell types within the heart. It is clear from genetic evidence that members of the paired box family and basic helix-loop-helix (bHLH) transcription factors from the twist family of proteins are expressed in and play an important function in cardiac neural crest specification and differentiation. Interestingly, both paired box and bHLH factors can function as dimers and in the case of twist family bHLH factors partner choice can clearly dictate a change in transcriptional program. The focus of this review is to consider the role that the protein-protein interactions of these transcription factors may play determining cardiac neural crest specification and differentiation and how genetic alteration of transcription factor stoichiometry within the cell may reflect more than a simple null event. Cardiovascular development and the role of the cardiac NCNeural crest cells become specified within the dorsal lip of the neural tube after which they migrate ventrally along the anterior posterior axis of the developing embryo and contribute to the formation of a variety of different tissues and organs including the skin, bone, neurons, and of course structures within the cardiovascular system. Deficiencies in cardiac neural crest cell (NC) development result in defective remodeling of the aortic arch arteries and failure of outflow tract septation. Development of a normally functioning heart and correctly remodeled vascular arterial system is required for embryonic viability (Winnier et al., 1999;Koushik et al., 2001;Conway et al., 2003), and the abnormal development of either of these aspects of the cardiovascular system can result in congenital heart defects that may be lethal or have costly lifelong effects.The importance of neural crest cell populations to the proper development of the heart and associated vasculature is evident from classical cell ablation studies done in the chick. In these experiments, ablation of neural crest migrating from rhombmeres 6-8 result in a number of congenital heart defects which include persistent trunks arteriosus (PTA), double outlet right ventricle (DORV), tetralogy of fallot (TOF), and ventricular septal defects (VSD) (Kirby, 1999). These experiments are difficult to perform in a mammalian system; however, the power of genetics in the mouse has provided for experimental approaches that have complimented the chick data. The identification of existing mutant mouse models, the creation of gene Please address correspondence to tfirulli@iupui.edu and siconway@iupui.edu. NIH Public Access Author ManuscriptBirth Defects Res C Embryo Today. Aut...

Gene Replacement Strategies to Test the Functional Redundancy of Basic Helix–Loop–Helix Transcription Factor

“…Although Hand1 and Hand2 are normally downregulated during embryogenesis by E13.5 and undetectable in newborns [6, 15, 16, 47], we did not detect any prolonged ectopic Hand2 expression in stillborn knock-in mutant hearts. Similarly, chamber-restricted gene Tbx20 also was not ectopically misexpressed, suggesting that Nppa and Ncx1 upregulation are indicative of heart failure rather than chamber identity/morphologic abnormalities.…”

“…Hand factors show high amino acid identity between species, suggesting conserved biologic function [6, 8, 9, 14, 15, 39], whereas functional studies have shown that Hand1 and Hand2 exhibit broad dimerization profiles [17]. Hand1 and Hand2 are evolutionarily conserved basic transcription factors that exhibit dynamic and partially overlapping spatiotemporal expression patterns during cardiovascular development.…”

“…Although mammalian Hand1 and Hand2 are initially coexpressed, during morphogenesis and asymmetric looping of the early embryonic heart tube, Hand1 becomes predominantly restricted to the left ventricle, whereas Hand2 becomes predominantly restricted to the right ventricle [16, 39]. However, both genes remain coexpressed in the embryonic aortic sac, the great vessels that exit the heart, and the nascent interventricular septum that eventually septates the left and right ventricular chambers [6, 15]. …”

A bHLH Code for Cardiac Morphogenesis

“…The bHLH factors Hand1 and Hand2 are members of the Twist-family of proteins and are broadly expressed throughout development in a number of tissues including: neural crest that contribute to craniofacial structures, sympathetic and enteric neurons and cardiac outflow tract (OFT); developing limbs; extraembryonic tissues; placenta and most significantly the cardiomyocytes [12, 13]. Hand mRNA is first detected around E7.5 throughout the cardiac crescent [8, 9, 22, 43].…”

Histone deacetylase 1 and 2 are essential for murine neural crest proliferation, pharyngeal arch development, and craniofacial morphogenesis

“…Mirroring the complex roles and derivatives of the NC, numerous congenital anomalies and syndromes have been mapped to defects in NCC function (Firulli and Conway, 2004; Verzi et al, 2007; Conway and Kaartinen, 2011; Bonilla-Claudio et al, 2012). Cranial NC abnormalities have been identified in patients with thymic aplasia (Ohnemus et al, 2002), palate defects (van Limborgh et al, 1983), and craniofacial malformations (Conway and Kaartinen, 2011).…”