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  • Review Article
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Building the mammalian heart from two sources of myocardial cells

Nature Reviews Genetics volume 6, pages 826–835 (2005)Cite this article

Key Points

  • Myocardial cells are derived from two sources — the classical first heart field and a recently described second heart field. The latter was identified on the basis of molecular markers and tracing of cell movements. Although the location and contribution to the heart differs, this second heart field has been described in both chick and mouse embryos.

  • Two myocardial cell lineages contribute to the formation of different regions of the heart and are distinguished by their colonization of the left ventricle and outflow tract, respectively. This has been revealed by a retrospective clonal analysis in the mouse embryo.

  • An increasing number of markers are emerging that demonstrate the molecular identity of the second heart field. The progenitor cells of the first heart field, on the other hand, remain poorly defined.

  • A reassessment of mutant phenotypes in the context of first and second heart fields leads to a better understanding of why the absence of a cardiac transcription factor results in the loss or reduction of a particular region of the heart.

  • Mutants in second heart-field genes and in sequences that control their expression reveal an extensive regulatory network that operates in these cardiac progenitor cells.

  • The effect of recent findings for the mouse embryo has major implications for the interpretation and classification of human heart defects. These have tended to be analysed in the context of the segmental model of cardiogenesis, which is now superseded by the concept of two heart fields and two myocardial cell lineages.

Abstract

Cardiogenesis is an exquisitely sensitive process. Any perturbation in the cells that contribute to the building of the heart leads to cardiac malformations, which frequently result in the death of the embryo. Previously, the myocardium was thought to be derived from a single source of cells. However, the recent identification of a second source of myocardial cells that make an important contribution to the cardiac chambers has modified the classical view of heart formation. It also has an important influence on the interpretation of mutant phenotypes in the mouse, with consequences for the classification and prognosis of human congenital heart defects.

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Figure 1: Morphogenesis of the mouse heart.
Figure 2: The segmental model of myocardial cell regionalization.
Figure 3: Two sources of myocardial cells in the developing heart.
Figure 4: Examples of mutant phenotypes that show first and second lineage defects.
Figure 5: Regulatory networks in the second heart field.

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Acknowledgements

We are grateful to members of the Buckingham laboratory for fruitful discussion. Work on cardiogenesis in the laboratory of M.B. is supported by grants from the Pasteur Institute and the Centre National de la Recherche Scientifique. S.M.M. is supported by a Marie Curie Intra-European Fellowship within the Sixth European Framework Programme.

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Author notes

  1. Sigolène Meilhac and Stéphane Zaffran: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Developmental Biology, CNRS URA 2578, Pasteur Institute, 25 Rue du Dr Roux, Paris, 75015, France

    Margaret Buckingham & Stéphane Zaffran

  2. Gurdon Institute, Tennis Court Road, Cambridge, CB2 1QN, United Kingdom

    Sigolène Meilhac

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  1. Margaret Buckingham
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DATABASES

Entrez Gene

Fgf8

Fgf10

Foxh1

Foxp4

GATA4

Hand1

Hand2

Isl1

Mef2c

MESP1

MESP2

NKX2-5

PITX2

Tbx1

Tbx5

Tbx20

OMIM

DiGeorge syndrome

Holt–Oram syndrome

Glossary

MYOCARDIUM

The striated muscle of the heart, which provides the contractile force that is necessary to pump blood around the body.

MESODERM

One of the three layers of cells in the early embryo that, together with the endoderm and ectoderm, provides the source of all subsequent cell types that appear during embryogenesis. Mesoderm gives rise to the skeletomuscular system, connective tissues, blood, and internal organs such as the heart.

PRIMITIVE STREAK

A transitory embryonic structure, which is present as a strip of cells, that pre-figures the anterior–posterior axis of the embryo. During gastrulation embryonic cells progress through the streak.

GASTRULATION

A crucial process in embryogenesis when major cellular movements lead to the involution of cells through the primitive streak, and subsequently give rise to the internal organs. As a result, the embryo contains three cell regions or germ layers: a middle layer of mesoderm surrounded by an outer layer of ectoderm and an inner layer of endoderm.

PHARYNGEAL MESODERM

The mesoderm that is situated below the head in the pharynx, which is the part of the embryo where the developing respiratory and digestive systems are present.

CHICK–QUAIL GRAFT

An experimental approach to studying cell fate that is based on the ability to distinguish between chick and quail cells and on the similar embryonic development of the two species. Cells can be transplanted from one to the other in ovo and their subsequent contribution to the developing embryo monitored.

PHARYNGEAL ARCHES

The embryonic structures that are present as a series of pouches that bud out from the pharynx. As development proceeds, the arches become incorporated into the different structures of the head or anterior trunk. The mesodermal core of the arches gives rise to cells that form anterior skeletal muscles and some myocardial progenitors.

DI-I LABELLING

A classical embryological approach to lineage tracing, which follows cell movement. The fluorescent dye Di-I is injected into cells of the embryo, which can subsequently be identified by stable labelling of their membranes.

RETROSPECTIVE CLONAL ANALYSIS

This is a genetic approach to lineage analysis that is based on random labelling of precursor cells. In the examples cited in this review, the method used a lacZ reporter carrying a duplication (laacZ) that renders it non-functional. Rare spontaneous intragenic recombination removes the duplication so that cells that express the reporter become β-galactosidase-positive, allowing clonal analysis.

NEURAL TUBE

A structure that is formed from ectoderm during neurulation. It extends from the brain to the posterior part of the body, and becomes the adult spinal cord. The neural tube also gives rise to motor neurons of the PNS.

CARDIAC BIFIDA

The presence of two totally or partially separated hearts, which is usually due to a failure of fusion of the cardiac crescent to form a single heart tube during embryogenesis.

HYPOPLASIA

This term is used to describe the reduced size of a tissue or organ that is due to a deficit in its cell population. During embryogenesis this may be due to a failure of a progenitor cell population to contribute to the tissue, or to a defect in proliferation or apoptosis.

NEURAL CREST CELLS

Progenitor cells present in vertebrates that arise from the dorsal neural tube and migrate to other sites in the embryo. These include the mesenchymal cells that contribute to septation in the heart.

CRE–LOXP SYSTEM

A genetic approach for producing conditional mutants or examining cell fate. This uses a specifically expressed Cre recombinase that recognizes loxP sites that are introduced into the gene to be targeted, which results in the recombination and removal of the intervening sequence between sites.

HISTONE METHYL TRANSFERASE

An enzyme that adds methyl groups to histones — DNA-binding proteins — that are involved in the regulation of gene accessibility to transcription. Their modification by methylation affects this function.

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Buckingham, M., Meilhac, S. & Zaffran, S. Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet 6, 826–835 (2005). https://doi.org/10.1038/nrg1710

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