Review
From the bottom of the heart: anteroposterior decisions in cardiac muscle differentiation

https://doi.org/10.1016/S0955-0674(00)00162-9Get rights and content

Abstract

Recently, studies on specification of axes in the developing embryo have focused on the heart, which is the first functional organ to form and probably responds to common cues controlling positional information in surrounding tissues. The early differentiation of heart cells affords an opportunity to link the acquisition of regional identity with the signals underlying terminal differentiation. In the past year, a wealth of information on these signals has emerged, elucidating the general pathways controlling body axes in the context of the developing heart.

Introduction

The differentiation of the vertebrate heart from an amorphous field of precursor cells must occur in a remarkably short time to provide a working circulatory system for the rapidly growing embryo. No other early differentiation event is more vital for survival. The complex pumping action of the heart relies on a spectacular chambered architecture, with marked asymmetry around every axis. Even small perturbations in its morphology produce profound deficits in cardiac performance. Once formed, the adult heart is incapable of rejuvenation. Cardiac muscle has only a limited period of postnatal proliferative potential, after which our hearts must beat continuously with the same myocyte population for the rest of our lives. There is no plasticity in the differentiated state of a mature cardiomyocyte.

It is important to keep these requisite properties in mind when building models of muscle-cell differentiation in the developing heart. Whatever the underlying mechanisms, assembly is quickly completed and tightly coordinated, and the resulting tissues differentiate early in gestation to generate an organ robust enough to survive in the absence of regenerative capacity. It follows that cardiac muscle-cell specification is likely to depend on the location and duration of signals governing more general developmental decisions in the early embryo.

During heart development, cardiac precursors are polarized along the three orthogonal axes (anteroposterior [AP], dorsoventral and mediolateral). The developing heart has been exploited to dissect the establishment of left/right asymmetry in the embryo; however, the specification of its AP polarity is equally critical because the heart must integrate into the incipient embryonic circulation, linking posterior cardiac structures with the venous system (inflow) and anterior cardiac structures with the arterial tree (outflow). Here we review recent results that suggest that AP patterning of the heart and its specification along other axes may, in fact, be controlled by common pathways.

Section snippets

Anteroposterior patterning

Precursor cells destined for the heart originate in the lateral epiblast and pass through the primitive streak to emerge as cardiogenic mesoderm, already specified as distinct cardiac lineages. Bilateral fields of cardiogenic mesoderm continue to migrate rostrally and eventually join at their anterior boundaries to form the cardiac crescent, where they commit irreversibly to a cardiac fate.

The AP patterning of the vertebrate heart is reflected in the original location of cardiogenic cells in

Waves of differentiation

The subsequent fusion of the cardiac crescent into a tube establishes a gradient of differentiation in which the more anterior cell groups are first to undergo myogenic differentiation as ventricles and outflow tract, and the more posterior cells subsequently differentiate to form the inflow structures (atria and sinus venosa). Even as overt left/right asymmetry is established by looping of the heart tube and formation of distinct chambers, posterior cardiac precursor cells continue to migrate

Transcriptional control of AP specification

In support of a progression of shifting signals, an increasing number of transcription factors have been identified in both mouse and chick that develop polarized expression patterns along the AP axis (reviewed in [2radical dotradical dot]). At the anterior pole, the iroquois-related homeobox protein Irx4 [3radical dot] and the hairy-related basic helix–loop–helix transcription factor HRT2 [4] first appear in the anterior cardiac crescent and soon become restricted to the section of primitive heart that gives rise to the

Retinoic acid in heart development

The restriction of transcription factors to different segments of the heart field provides insight into the regulatory intermediates underlying AP identities and can be used to identify potential downstream gene targets, but the control of their expression must be integrated with the spatial and temporal features of general AP specification in the early embryo as a whole.

Retinoic acid (RA) has long been appreciated as an important signaling morphogen in early embryogenesis, and RA excess or

Localized control of RA synthesis

Retinoic acid is produced endogenously by a series of oxidative reactions that convert vitamin A to active retinoids. Expression of the synthetic enzyme retinaldehyde dehydrogenase type 2 (RALDH2), the sole source of RA in the early embryo [19], is restricted to the posterior lateral plate mesoderm, excluding the node in both mouse and chick embryos [20], [21], [22 A close correlation between RA synthesis and responsiveness, shown either with a general RA-activated transgenic reporter [23] or

Conclusions: specification from the bottom of the heart

The collective studies on early specification of cardiac AP identities are consistent with a model in which positional information along the AP axis is controlled, at least in part, by localized production of RA. The model is dynamic: cardiac precursors migrating through the primitive streak are not subject to RA signaling before mid-to-late gastrulation (E7.5 in the mouse, stages 5–6 in the chick), when RALDH2 is first expressed in the mesoderm posterior and lateral to the node. Thus,

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • radical dot of special interest

  • radical dotradical dot of outstanding interest

References (29)

  • J Moss et al.

    Dynamic patterns of retinoic acid synthesis and response in the developing mammalian heart

    Dev Biol

    (1998)
  • L Ehrman et al.

    Lack of regulation inf the heart forming region of avian embryos

    Dev Biol

    (1999)
  • M Zile et al.

    Retinoid signaling is required to complete the vertebrate cardiac left/right asymmetery pathway

    Dev Biol

    (2000)
  • G Rosenquist et al.

    Migration of precardiac cells in the chick embryo: a radioautographic study

    Carnegie Contrib Embryol

    (1966)
  • Cited by (47)

    • Cell therapy approaches for treatment of bradyarrhythmias

      2020, Emerging Technologies for Heart Diseases: Volume 2: Treatments for Myocardial Ischemia and Arrhythmias
    • Human Pluripotent Stem Cell-Derived Atrial and Ventricular Cardiomyocytes Develop from Distinct Mesoderm Populations

      2017, Cell Stem Cell
      Citation Excerpt :

      The heart develops from mesodermal cells that migrate anterolaterally from the primitive streak to a position under the developing headfold where they form an epithelial structure known as the cardiac crescent (Buckingham et al., 2005; Christoffels et al., 2000). This crescent fuses at the midline to establish the primitive heart tube that is patterned along the anterior-posterior axis to form distinct anterior and posterior poles containing progenitors that give rise to different regions of the adult organ (Christoffels et al., 2000; Rosenthal and Xavier-Neto, 2000; Vincent and Buckingham, 2010). The anterior progenitors differentiate first and give rise to the ventricles, whereas those positioned in the posterior pole differentiate at a slightly later time and contribute to the atria and sinus venosa (Bruneau et al., 2000; Rosenthal and Xavier-Neto, 2000; Vincent and Buckingham, 2010).

    • Cardiovascular Development

      2017, Fetal and Neonatal Physiology, 2-Volume Set
    View all citing articles on Scopus
    View full text