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A bHLH Code for Cardiac Morphogenesis

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Abstract

Cell specification and differentiation of cardiomyocytes from mesodermal precursors is orchestrated by epigenetic and transcriptional inputs throughout heart formation. Of the many transcription factor super families that play a role in this process, the basic Helix-loop Helix (bHLH) family of proteins is well represented. The bHLH protein by design allows for dimerization—both as homodimers and heterodimers with other proteins within the family. Although DNA binding is mediated via a short variable cis-element termed an E-box, it is clear that DNA-affinity for these elements as well as the transcriptional input conveyed is dictated largely by the transcriptional partners within the dimer complex. Dimer partner choice has a number of inputs requiring co-expression within a given cell nucleus and dimerization modulation by the level of protein present, and post-translational modifications that can both enhance or reduce protein–protein interactions. Due to these complex interrelationships, it has been difficult to identity bona-fide downstream transcriptional targets and define the molecular pathways regulated of bHLH factors within cardiogenesis, despite the clear roles suggested via loss-of-function animals models. This review focuses on the Hand bHLH proteins—key members of the Twist-family of bHLH factors. Despite over a decade of investigation, questions regarding functional redundancy, downstream targets, and biological role during heart specification and differentiation have still not been fully addressed. Our goal is to review what is currently known and address strategies for gaining further understanding of Hand/Twist gene dosage and functional redundancy relationships within the developing heart that may underlie congenital heart defect pathogenesis.

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Acknowledgments

We would like to thank members of the Firulli and Conway labs for scientific assistance. We would also like to thank the Riley Heart Research Center for helpful input during robust group discussions. Support is provided by the Herman B Wells Center for Pediatric Research, the Riley Children’s Foundation, and the Division of Pediatric Cardiology and by NIH P01HL085098 (ABF & SJC).

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  1. Division of Pediatric Cardiology, Departments Anatomy and Medical and Molecular Genetics, Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W. Walnut St, Indianapolis, IN, 46202-5225, USA

    Simon J. Conway, Beth Firulli & Anthony B. Firulli

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  1. Simon J. Conway
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  2. Beth Firulli
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Correspondence to Anthony B. Firulli.

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Conway, S.J., Firulli, B. & Firulli, A.B. A bHLH Code for Cardiac Morphogenesis. Pediatr Cardiol 31, 318–324 (2010). https://doi.org/10.1007/s00246-009-9608-x

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