HAND Proteins: Molecular Mediators of Cardiac Development and Congenital Heart Disease

doi:10.1016/S1050-1738(98)00033-4

Trends in Cardiovascular Medicine

Volume 9, Issues 1–2, January–February 1999, Pages 11-18

https://doi.org/10.1016/S1050-1738(98)00033-4 Get rights and content

Abstract

Congenital heart defects are the clinical manifestation of anomalies in embryonic cardiac development. Such defects occur in distinct regions or chambers of the heart. A molecular framework in which to consider cardiac development and congenital heart disease in a segmental fashion has begun to emerge. dHAND and eHAND are two related basic helix-loop-helix transcription factors that are expressed in a complementary fashion in the developing right and left ventricles, respectively. They are also expressed in the neural crest-derived cardiac outflow tract and aortic arch arteries. Targeted mutations of dHAND and eHAND in mice have revealed novel pathways of organogenesis in mesodermal and neural crest derivatives. dHAND mutants exhibit hypoplasia of the right ventricle, branchial arches, and aortic arch arteries. The distinct nature of cardiac defects in dHAND mutants provides an entry into dissecting molecular pathways governing morphogenesis of specific components of the heart. Congenital heart disease is considered as a defect in segmental development of the heart and the role of dHAND and eHAND in regulating such developmental pathways in normal and abnormal cardiogenesis is examined.

Section snippets

Cardiac Morphogenesis: Mesodermal and Neural Crest Contributions

There are relevant anatomical and embryologic features of heart development that contribute to an understanding of the molecular pathways in which the HAND genes are involved. Two major cell types that contribute to the heart will be considered: lateral mesodermal cells and ectodermal cells derived from the neural crest. Both cell types have unique embryologic origins yet must coordinate with one another as the heart takes its final form.

The muscular portion of the heart is derived from

Expression Pattern of dHAND and eHAND

dHAND and eHAND share high homology within their bHLH regions and are encoded by genes with similar intron-exon organization, suggesting that the genes arose by duplication of an ancestral HAND-like gene. In the chick (Srivastava et al. 1995), dHAND and eHAND are coexpressed in a bilaterally symmetric pattern throughout the precardiac mesoderm, linear and looped heart tube, lateral mesoderm and certain neural crest-derived structures. Antisense experiments in the chick suggest that dHAND and

Targeted Deletion of dHAND in Mice

Significant insight into the role of the dHAND gene in cardiogenesis has come from mouse knockout studies. Heterozygote dHAND-null mice survive to reproductive age, but homozygous null mice die by embryonic day (E) 11.0, apparently from cardiac failure (Srivastava et al. 1997). dHAND-null embryos begin the process of cardiac looping in the rightward direction, but fail to develop the segment of the heart tube that forms the right ventricle (Figure 3A, B). This is consistent with the predominant

Targeted Deletion of eHAND in Mice

The eHAND gene has recently been disrupted in mice by two independent groups Firulli et al. 1998, Riley et al. 1998. eHAND-null embryos had early embryonic lethality secondary to defects in placentation, making analysis of eHAND’s role in cardiac morphogenesis ambiguous. Nevertheless, like dHAND, eHAND did not appear to be required for differentiation of cardiomyocytes based on expression of cardiac markers and chimeric analysis. Trophoblast rescue using tetraploid embryos allowed embryo growth

Role of HAND Genes in Left-Right Asymmetry

The complementary expression of dHAND and eHAND in the right and left ventricles, respectively, has produced some confusion regarding the role of the HAND proteins in left-right (LR) embryonic asymmetry. Work in recent years has identified numerous signaling molecules and transcription factors, including sonic hedgehog, nodal, activin, snail, and others, which are expressed in a LR asymmetric fashion prior to heart formation and control embryonic LR asymmetry [reviewed in Levin (1997),

HAND Genes Mediate Signaling in Neural Crest-Derived Cells

Mice deficient in the signaling peptide, endothelin-1 (ET-1), which functions through a G protein-coupled cell surface receptor, had defects of neural crest-derived cells Kurihara et al. 1994, Kurihara et al. 1995. Specifically, defects were seen in tissues derived from the branchial arches, including craniofacial structures, and the cardiac neural crest. The ET-1-null phenotype is remarkably similar to the clinical condition known as DiGeorge syndrome, where affected individuals have

Mechanism of Action of dHAND

Dissection of the molecular pathways in which the HAND genes function has begun to clarify the developmental programs operative in distinct regions of the heart. The next challenge will be to determine the cell biology and mechanistic features of critical developmental steps during cardiac morphogenesis. Further analysis of the dHAND-null phenotype, has recently provided some insight into the cell biology of dHAND’s developmental pathway. Careful tracing of cell fate indicates that dHAND is not

Clinical Implications of the HAND Pathways

Beyond understanding the basic biologic principles through which the HAND proteins and other members of their pathway act, the type of efforts described here should ultimately result in identification of genes that, when mutated or deleted, cause CHD. An example of this was recently seen where Nkx2.5, the homeo-box gene upstream of eHAND, was found to be mutated in families with atrial septal defects and atrio-ventricular node defects (Schott et al. 1998). Based on our experiments in mice, it

Future Prospects

The studies reviewed here on the HAND genes exemplify the power of dissecting molecular pathways of organogenesis in the interest of basic science and human disease. However, many important questions remain in understanding the role of the HAND proteins in cardiogenesis and CHD. What are the target genes that lie downstream of these transcription factors and what are their mechanisms of action? What factors lie upstream of dHAND and eHAND and control the chamber-specific expression patterns

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Cited by (84)

Hypoplastic Left Heart Syndrome Across the Lifespan: Clinical Considerations for Care of the Fetus, Child, and Adult
2022, Canadian Journal of Cardiology
Citation Excerpt :
A second group of genes of potential interest are those that encode transcription factors considered to be essential for cardiac morphogenesis. One such example is Hand1, a basic helix-loop-helix transcription factor that contributes to the balance between cardioblast proliferation and differentiation.16-18 Given its essential role in LV development, Hand1 may be considered a strong candidate gene for HLHS pathogenesis.
Hypoplastic left heart syndrome (HLHS) is the most common anatomic lesion in children born with single-ventricle physiology and is characterised by the presence of a dominant right ventricle and a hypoplastic left ventricle along with small left-sided heart structures. Diagnostic subgroups of HLHS reflect the extent of inflow and outflow obstruction at the aortic and mitral valves, specifically stenosis or atresia. If left unpalliated, HLHS is a uniformly fatal lesion in infancy. Following introduction of the Norwood operation, early survival has steadily improved over the past 4 decades, mirroring advances in operative and perioperative management as well as reflecting refinements in patient surveillance and interstage clinical care. Notably, survival after staged palliation has increased from 0% to a 5-year survival of 60%-65% for children in some centres. Despite the prevalence of HLHS in childhood with relatively favourable surgical outcomes in contemporary series, this cohort is only now reaching early adult life and longer-term outcomes have yet to be elucidated. In this article we focus on contemporary clinical management strategies for patients with HLHS across the lifespan, from fetal to adult life. Nomenclature and diagnostic considerations are discussed and current literature pertaining to putative genetic etiologies is reviewed. The spectrum of fetal and paediatric interventional strategies, both percutaneous and surgical, is described. Clinical, patient-reported, and neurodevelopmental outcomes of HLHS are delineated. Finally, note is made of current areas of clinical uncertainty, and suggested directions for future research are highlighted.
Le syndrome d’hypoplasie du cœur gauche (SHCG) est la lésion anatomique la plus fréquente chez les enfants présentant un cœur univentriculaire. Il se caractérise par la présence d’un ventricule droit dominant, d’un ventricule gauche hypoplasique et d’un sous-développement structurel du côté gauche du cœur. Les sous-groupes diagnostiques du SHCG reflètent l’étendue de l’obstruction des voies d’admission et d’éjection au niveau des valves aortique et mitrale, en particulier une sténose ou une atrésie. Sans traitement palliatif, le SHCG provoque invariablement le décès des enfants dans leurs premières années de vie. L’avènement de l’intervention de Norwood a permis une amélioration constante de la survie aux stades initiaux durant les quatre dernières décennies. Ce constat dénote les progrès réalisés dans la prise en charge opératoire et périopératoire ainsi que les améliorations apportées à la surveillance des patients et aux soins cliniques intermédiaires. Ainsi, d’un taux de survie de 0 % après une palliation par étapes, nous sommes passés à un taux de survie de 60 % à 65 % à 5 ans chez les enfants dans certains établissements. Malgré la fréquence du SHCG chez les enfants et l’issue relativement favorable de son traitement chirurgical de nos jours, cette cohorte commence à peine à atteindre le début de l’âge adulte, et le devenir des patients à plus long terme demeure incertain. Dans le présent article, nous mettons en lumière les stratégies contemporaines de prise en charge clinique des patients atteints du SHCG tout au long de leur existence, de la vie fœtale à la vie adulte. Nous abordons aussi des considérations touchant la nomenclature et le diagnostic, et passons en revue les publications consacrées aux causes génétiques présumées. Par ailleurs, nous décrivons l’éventail des stratégies interventionnelles fœtales et pédiatriques, tant percutanées que chirurgicales. Nous caractérisons également l’issue du SHCG sur les plans clinique et neurodéveloppemental, ainsi que d’après les données d’autodéclaration des patients. Enfin, nous signalons des aspects cliniques qui restent à préciser et mettons en avant quelques avenues de recherche.
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This chapter focuses on determination and differentiation of skeletal muscle as a paradigm for how tissues differentiate in development and regeneration. Classical embryological concepts that emerged from descriptive embryology are explained and cast in genetic and molecular biological terms. An understanding of the mechanistic basis of embryonic commitment to a unique developmental pathway, and the subsequent realization of the adult phenotypes, are essential for understanding stem cell behavior and how stem cells might be manipulated for therapeutic purposes. The importance of satellite, or stem cells, in skeletal muscle formation and regeneration of skeletal muscle and the role of microRNAs and transcription factors in these processes are illustrated. The challenge of regeneration of anatomic muscles to repair damage from disease and trauma requires an understanding of fundamental mechanisms in skeletal muscle formation.
The regulation of embryo implantation and endometrial decidualization by progesterone receptor signaling
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During the early stages of pregnancy, fertilized embryos must attach to the uterine epithelium, invade into the underlying uterine stroma, and the stroma must then differentiate in a process termed decidualization in order for a successful pregnancy to be initiated. The steroid hormone progesterone (P4) is an integral mediator of these early pregnancy events, exerting its effects via the progesterone receptor (PR). Insights gained from the use of mouse models and genomic profiling has identified many of the key molecules enlisted by PR to execute the paradigm of early pregnancy. This review describes several of the molecules through which the PR exerts its pleiotropic effects including ligands, receptors, chaperones, signaling proteins and transcription factors. Understanding these molecules and their concatenation is of vital importance to our ability to clinically treat reproductive health problems like infertility and endometriosis.
Left ventricular hypoplasia: A spectrum of disease involving the left ventricular outflow tract, aortic valve, and aorta
2012, Journal of the American College of Cardiology
Citation Excerpt :
Both HAND-1 and HAND-2 are coexpressed uniformly in the cardiac crescent of the primary heart field (25). During initial development of the heart tube, their expression is again fairly uniform, but marked differences in expression are then seen in the craniocaudal axis in a ventricle-specific fashion (25) (leading to left–right asymmetry after looping) (Fig. 4). HAND-1 transcripts are detected particularly in the conus arteriosus, truncus arteriosus, primitive atrium, and primitive ventricle, but expression is notably deficient in the bulbus cordis (the future right ventricle).
“Hypoplastic left heart syndrome” is an unsatisfactory term describing lethal underdevelopment of the left ventricle (LV). It represents the more severe end of a spectrum of LV hypoplasia, mandating single-ventricle palliation or cardiac transplantation. Less severe “borderline” ventricular hypoplasia may instead allow various biventricular therapeutic strategies and better long-term outcomes. In this review, we consider factors causing and modifying the abnormal development of the LV. LV hypoplasia is typically seen in association with left ventricular outflow tract obstruction, itself part of a spectrum of related defects with common etiologies. Secondary responses to outflow obstruction are complex but involve abnormal flow dynamics and shear stresses that result in compromised and poorly orchestrated ventricular growth and development. Subsequent remodeling is likely influenced by genetic modifiers, including intrinsic myocardial growth signaling pathways, possibly including those of HAND transcription factors. In addition, during the latter stages of gestation, cardiomyocytes undergo a switch in myogenic potential and lose the ability to undergo mitosis. Ventricular hyperplasia can therefore no longer occur; remodeling is instead limited to muscular hypertrophy. Subtle differences in this switch in myogenic potential—and modulators thereof—are likely to be of clinical and therapeutic importance, especially in children with “borderline LVs” being considered for fetal interventions or post-natal biventricular repair strategies. Finally, by more clearly understanding the initiators and propagators of abnormal ventricular development, we can hope to lean away from grouping a heterogeneous group of infants together under the unsatisfactory term “hypoplastic left heart syndrome.”

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ArticlesHAND Proteins: Molecular Mediators of Cardiac Development and Congenital Heart Disease

Abstract

Section snippets

Cardiac Morphogenesis: Mesodermal and Neural Crest Contributions

Expression Pattern of dHAND and eHAND

Targeted Deletion of dHAND in Mice

Targeted Deletion of eHAND in Mice

Role of HAND Genes in Left-Right Asymmetry

HAND Genes Mediate Signaling in Neural Crest-Derived Cells

Mechanism of Action of dHAND

Clinical Implications of the HAND Pathways

Future Prospects

The clinical and genetic spectrum of the Holt-Oram syndrome

N Engl J Med

Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome

Nat Genet

Homeodomain factor Nkx2-5 controls left/right asymmetric expression of bHLH gene eHAND during murine heart development

Genes & Dev

Hxt encodes a basic helix-loop-helix transcription factor that regulates trophoblast cell development

Development

Expression of the novel basic helix-loop-helix gene eHAND in neural crest derivatives and extraembryonic membranes during mouse development

Dev Biol

Prevalence of 22q11 microdeletions in Di-George and velocardiofacial syndromesim-plications for genetic counseling and prenatal diagnosis

J Med Genet

Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand 1

Nature Genet

Fashioning the vertebrae heartearliest embryonic decisions

Development

Fontan operation in five hundred consective patientsfactors influencing early and late outcome

J Thorac Cardiovasc Surg

Experimental production of hypoplastic left heart syndrome in the chick embryo

Pediatric Cardiology

NK-2 homeobox genes and heart development

Dev Biol

Incidence of congenital heart diseaseI, Postnatal incidence

Pediat Cardiol

Identification of a new family of tissue-specific basic helix-loop helix proteins with a two-hybrid system

Mol Cell Biol

Myosin light chain 3F regulatory sequences confer regionalized cardiac and skeletal muscle expression in transgenic mice

J Cell Biol

Role of neural crest in congenital heart disease

Circulation

Neural crest and cardiovascular patterning

Circ Res

A single MEF2 site governs desmin transcription in both heart and skeletal muscle during mouse embryogenesis

Dev Biol

GATA4 transcription factor is required for ventral morphogenesis and heart tube formation

Genes Dev

Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1

Nature

Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1

J Clin Inv

Left-right asymmetry in vertebrate embryogenesis

Bioessays

Articles
HAND Proteins: Molecular Mediators of Cardiac Development and Congenital Heart Disease