Hand factors as regulators of cardiac morphogenesis and implications for congenital heart defects

Abstract

Almost 15 years of careful study have established the related bHLH transcription factors Hand1 and Hand2 as critical for heart development across evolution. Hand factors make broad contributions, revealed through animal models, to the development of multiple cellular lineages that ultimately contribute to the heart. They perform critical roles in ventricular cardiomyocyte growth, differentiation, morphogenesis, and conduction. They are also important for the proper development of the cardiac outflow tract, epicardium, and endocardium. Molecularly, they function both through DNA-binding and through protein-protein interactions, which are regulated transcriptionally, post-transcriptionally by microRNAs, and post-translationally through phospho-regulation, Although direct Hand factor transcriptional targets are progressively being identified, confirmed direct targets of Hand factor transcriptional activity in the heart are limited. Identification of these targets will be critical to model the mechanisms by which Hand factor bHLH interactions affect developmental pathways. Improved understanding of Hand factor-mediated transcriptional cascades will be necessary to determine how Hand factor disregulation translates to human disease phenotypes. The following review summarizes the insight animal models have provided into the regulation and function of these factors during heart development, and the recent findings that suggest roles for HAND1 and HAND2 in human congenital heart disease.

Effect of Human Donor Cell Source on Differentiation and Function of Cardiac Induced Pluripotent Stem Cells

“…MESP1 is a transcription factor necessary for the specification of multipotent cardiovascular progenitors and the expression of cardiovascular transcription factors (13). HAND2 is a transcription factor involved in heart development (14), whereas MYOCD is a transcriptional co-activator of Serum Response Factor (SRF), which interacts with TBX5 to promote cardiac gene expression (15). GATA4 is a co-activator of NKX2-5 (16), a transcription factor involved in heart formation and development (17).…”

Transcriptional networks regulating the costamere, sarcomere, and other cytoskeletal structures in striated muscle

“…The bHLH transcription factor Hand1 is required for the differentiation of myocardial and non-myocardial cell types in the developing heart (115). While Hand1 function has been analyzed primarily in early cardiogenic events, cardiac overexpression of Hand1 in adult transgenic mice results in cardiac arrhythmias in adult mice (116).…”

HAND2 Targets Define a Network of Transcriptional Regulators that Compartmentalize the Early Limb Bud Mesenchyme

“…Hand2 is genetically required for limb bud, branchial arch and heart development and the lethality of Hand2 -deficient mouse embryos around embryonic day E9.5 is caused by the severe heart malformations (Srivastava et al, 1997; Vincentz et al, 2011). During early limb bud development, Hand2 is required for AP polarization of the nascent limb bud mesenchyme and activation of Shh expression as part of its genetic interactions with Gli3 (Charité et al, 2000; Galli et al, 2010).…”