Hand Factors As Regulators of Cardiac Morphogenesis and Implications for Congenital Heart Defects

Overview

Journal Birth Defects Res A Clin Mol Teratol

Publisher Wiley

Date 2011 Apr 5

PMID 21462297

Citations 35

Authors

Joshua W Vincentz

Ralston M Barnes

Anthony B Firulli

Affiliations

Soon will be listed here.

Abstract

Almost 15 years of careful study have established the related basic Helix-Loop-Helix (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, posttranscriptionally by microRNAs, and posttranslationally through phosphoregulation. 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 dysregulation translates to human disease phenotypes. This review summarizes the insight that animal models have provided into the regulation and function of these factors during heart development, in addition to the recent findings that suggest roles for HAND1 and HAND2 in human congenital heart disease.

Citing Articles

PDGFRA is a conserved HAND2 effector during early cardiac development.

Xu Y, Gehlot R, Capon S, Albu M, Gretz J, Bloomekatz J Nat Cardiovasc Res. 2024; 3(12):1531-1548.

PMID: 39658721 PMC: 11634778. DOI: 10.1038/s44161-024-00574-1.

Fibronectin and Hand2 influence tubulogenesis during pronephros development and mesonephros regeneration in zebrafish (Danio rerio).

Uribe-Montes L, Sanabria-Camargo C, Pineros-Romero C, Otalora-Tarazona S, Avila-Jimenez E, Acosta-Virguez E PLoS One. 2024; 19(9):e0307390.

PMID: 39240899 PMC: 11379296. DOI: 10.1371/journal.pone.0307390.

Molecular and cellular role of variants of the promoter region of HAND1 gene in sporadic and isolated ventricular septal defect.

Qi J, Chen H, Hou H, Chen Z, Liu L, Yang Q Mol Cell Biochem. 2024; 480(3):1657-1667.

PMID: 39107573 DOI: 10.1007/s11010-024-05088-9.

Role of Genetic Variation in Transcriptional Regulatory Elements in Heart Rhythm.

Jonker T, Barnett P, Boink G, Christoffels V Cells. 2024; 13(1).

PMID: 38201209 PMC: 10777909. DOI: 10.3390/cells13010004.

The benign nature and rare occurrence of cardiac myxoma as a possible consequence of the limited cardiac proliferative/ regenerative potential: a systematic review.

Shafi O, Siddiqui G, Jaffry H BMC Cancer. 2023; 23(1):1245.

PMID: 38110859 PMC: 10726542. DOI: 10.1186/s12885-023-11723-3.

References

Waldo K, Miyagawa-Tomita S, Kumiski D, Kirby M . Cardiac neural crest cells provide new insight into septation of the cardiac outflow tract: aortic sac to ventricular septal closure. Dev Biol. 1998; 196(2):129-44. DOI: 10.1006/dbio.1998.8860. View

Huang J, Bridges L, White J . Selective modulation of integrin-mediated cell migration by distinct ADAM family members. Mol Biol Cell. 2005; 16(10):4982-91. PMC: 1237097. DOI: 10.1091/mbc.e05-03-0258. View

Togi K, Kawamoto T, Yamauchi R, Yoshida Y, Kita T, Tanaka M . Role of Hand1/eHAND in the dorso-ventral patterning and interventricular septum formation in the embryonic heart. Mol Cell Biol. 2004; 24(11):4627-35. PMC: 416422. DOI: 10.1128/MCB.24.11.4627-4635.2004. View

Hendershot T, Liu H, Sarkar A, Giovannucci D, Clouthier D, Abe M . Expression of Hand2 is sufficient for neurogenesis and cell type-specific gene expression in the enteric nervous system. Dev Dyn. 2006; 236(1):93-105. DOI: 10.1002/dvdy.20989. View

Wills A, Holdway J, Major R, Poss K . Regulated addition of new myocardial and epicardial cells fosters homeostatic cardiac growth and maintenance in adult zebrafish. Development. 2007; 135(1):183-92. DOI: 10.1242/dev.010363. View

Conway S, Firulli B, Firulli A . A bHLH code for cardiac morphogenesis. Pediatr Cardiol. 2009; 31(3):318-24. PMC: 2837108. DOI: 10.1007/s00246-009-9608-x. View

Firulli A, McFADDEN D, Lin Q, Srivastava D, Olson E . Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand1. Nat Genet. 1998; 18(3):266-70. DOI: 10.1038/ng0398-266. View

Firulli A . A HANDful of questions: the molecular biology of the heart and neural crest derivatives (HAND)-subclass of basic helix-loop-helix transcription factors. Gene. 2003; 312:27-40. DOI: 10.1016/s0378-1119(03)00669-3. View

McFadden D, Barbosa A, Richardson J, Schneider M, Srivastava D, Olson E . The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner. Development. 2004; 132(1):189-201. DOI: 10.1242/dev.01562. View

10.

Byatt S, Baker E, Richards R, Roberts C, Smith A . Unbalanced t(4;11)(q32;q23) in a 34-year-old man with manifestations of distal monosomy 11q and trisomy 4q syndromes. Am J Med Genet. 1997; 70(4):357-60. View

11.

Schatteman G, Bork T, Bowen-Pope D, Weston J . A PDGF receptor mutation in the mouse (Patch) perturbs the development of a non-neuronal subset of neural crest-derived cells. Development. 1992; 115(1):133-42. DOI: 10.1242/dev.115.1.133. View

12.

Stoller J, Epstein J . Cardiac neural crest. Semin Cell Dev Biol. 2005; 16(6):704-15. DOI: 10.1016/j.semcdb.2005.06.004. View

13.

Liu J, Stainier D . Tbx5 and Bmp signaling are essential for proepicardium specification in zebrafish. Circ Res. 2010; 106(12):1818-28. PMC: 2892550. DOI: 10.1161/CIRCRESAHA.110.217950. View

14.

Vincentz J, Barnes R, Rodgers R, Firulli B, Conway S, Firulli A . An absence of Twist1 results in aberrant cardiac neural crest morphogenesis. Dev Biol. 2008; 320(1):131-9. PMC: 2572997. DOI: 10.1016/j.ydbio.2008.04.037. View

15.

Risebro C, Smart N, Dupays L, Breckenridge R, Mohun T, Riley P . Hand1 regulates cardiomyocyte proliferation versus differentiation in the developing heart. Development. 2006; 133(22):4595-606. DOI: 10.1242/dev.02625. View

16.

Srivastava D, Olson E . A genetic blueprint for cardiac development. Nature. 2000; 407(6801):221-6. DOI: 10.1038/35025190. View

17.

Rychlik J, Gerbasi V, Lewis E . The interaction between dHAND and Arix at the dopamine beta-hydroxylase promoter region is independent of direct dHAND binding to DNA. J Biol Chem. 2003; 278(49):49652-60. DOI: 10.1074/jbc.M308577200. View

18.

Gutstein D, Morley G, Vaidya D, Liu F, Chen F, Stuhlmann H . Heterogeneous expression of Gap junction channels in the heart leads to conduction defects and ventricular dysfunction. Circulation. 2001; 104(10):1194-9. DOI: 10.1161/hc3601.093990. View

19.

Dupont E, Matsushita T, Kaba R, Vozzi C, Coppen S, Khan N . Altered connexin expression in human congestive heart failure. J Mol Cell Cardiol. 2001; 33(2):359-71. DOI: 10.1006/jmcc.2000.1308. View

20.

Smart N, Hill A, Cross J, Riley P . A differential screen for putative targets of the bHLH transcription factor Hand1 in cardiac morphogenesis. Gene Expr Patterns. 2003; 2(1-2):61-7. DOI: 10.1016/s0925-4773(02)00380-5. View