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(Circulation Research. 1995;77:216-219.)
© 1995 American Heart Association, Inc.

Articles

Diversification of Cardiomyogenic Cell Lineages During Early Heart Development

Katherine E. Yutzey, David Bader

From the Department of Cell Biology and Anatomy, Cornell University Medical College, New York, NY.

Correspondence to Dr David Bader, Vanderbilt University School of Medicine, MRBII, Nashville, TN 37232.

Key Words: cardiac myogenesis • myogenic diversification • embryogenesis

	Introduction

Top Introduction Where Are Atrial and... When Are Atrial and... When Are Atrial and... What Regulatory Mechanisms Are... Summary References

 
The vertebrate heart is composed of a limited number of well-characterized cell types and therefore is an excellent system in which to study lineage-determination events and organogenesis. The diversification of atrial and ventricular myogenic lineages is evident in the morphology, physiology, and molecular composition of the fully formed heart and is essential to the circulatory and endocrine functions of the heart. Recent work from our laboratory and others has examined the origins of the atrial and ventricular myocyte cell lineages from the earliest stages of development. These studies have addressed where these lineages arise in the early vertebrate embryo, when diversified cell lineages are first evident in the primitive heart, and what mechanisms result in the separation of these lineages. Much of the information regarding myocyte lineage diversification has been obtained by study of the early chicken embryo because of its accessibility and potential for embryological manipulation. Additional studies in the mouse, frog, and zebra fish have significantly advanced our knowledge of early vertebrate cardiogenesis. Taken together, these studies demonstrated that the separation of atrial and ventricular myogenic lineages occurs before heart chamber formation and that the determination of these lineages is primarily based on the anteroposterior polarity of the heart progenitors in the very early embryo. In the present communication, we review the origins of the lineages and molecular events involved in generating atrial and ventricular myocyte populations.

	Where Are Atrial and Ventricular Precursors Located?

Top Introduction Where Are Atrial and... When Are Atrial and... When Are Atrial and... What Regulatory Mechanisms Are... Summary References

 
The chicken has been used as a model system in which to study the organogenesis of the heart in vertebrates.¹ Fate-mapping studies of the early chicken embryo have followed the origins of the cardiovascular system from the very earliest stages of embryogenesis and have determined that the cells that will become the heart are one of the first mesodermal cell types to emerge from the primitive streak (Figure, panel A).² During gastrulation, the cardiac precursors are present in the rostral half of the primitive streak, caudal to Hensen's node during stages 3 to 3+.⁵ The newly gastrulated mesoderm migrates anteriorly and laterally to the position of the anterior lateral plate mesoderm, where it condenses into bilaterally placed cardiogenic crescents during the first 24 to 30 hours of development in the chicken.⁶ Fate-mapping studies have indicated that the relative positions of progenitor cells do not change as they migrate or as they reside in the cardiogenic crescents; therefore, anteroposterior positions within cardiogenic mesoderm are probably established during gastrulation.^{6 7} Lateral plate mesoderm removed from embryos at the late primitive streak stage will differentiate into cardiac myocytes in vitro, demonstrating that specification of the cardiac lineage has occurred by this time.⁸ The anteroposterior position of gastrulating precardiac cells is later reflected in the relative positions of these cells in the newly formed heart tube, with the more anteriorly gastrulating cells residing in the anterior segments of the heart tube and more posteriorly gastrulating cells residing in the posterior segments.² As development continues (stages 6 to 10), cardiogenic mesoderm present in the anterior splanchnic mesoderm epithelializes and forms bilaterally placed tubular cardiac primordia. The folding of the embryo that creates the head fold and lateral body folds brings these primordia to posterior and medial locations, where they fuse to form a midline tubular structure.¹ Fusion of the primitive heart tube is accompanied by the anterior to posterior activation of cardiac-specific gene expression.^{4 9} Morphogenesis of the heart continues during days 3 and 4 of development as the primitive heart tube elongates and looping of the heart tube causes the posterior region to move dorsally and cranially. Subsequently, the valves and septa form, generating the four-chambered heart. Fate-mapping analysis of the cardiac primordia and primitive heart tube has demonstrated that the ventricles are derived from the anterior cardiac precursors and the atria arise from the posterior heart-forming region.^{1 10} Therefore, relative positions of the ventriculogenic and atriogenic populations of cardiac progenitors are maintained along the anteroposterior axis from gastrulation to the formation of the chambered heart.

View larger version (30K): [in this window] [in a new window]   Figure 1. Localization of diversified cardiomyogenic cell lineages during early heart development. A, Fate-mapping studies identified preventricular (stippled) and preatrial (solid) populations of undifferentiated cardiac progenitors at stage 3,2 stage 4,3 and stage 7.1 B, Atrial-specific gene expression (solid) is evident within the differentiated myocardium (stippled and solid) beginning at stage 9.4

	When Are Atrial and Ventricular Lineages Evident?

Top Introduction Where Are Atrial and... When Are Atrial and... When Are Atrial and... What Regulatory Mechanisms Are... Summary References

 
Fate-mapping studies of the early embryo did not distinguish morphologically or molecularly between diversified atrial and ventricular lineages. Immunolabeling studies using monoclonal antibodies directed against different isoforms of myosin heavy chain led to early detection of diversified myogenic lineages. Expression of an atrial-specific myosin isoform was first detected in the posterior heart tube at stage 15, before valve formation and septation.¹¹ Further analysis demonstrated that an atrial-specific myosin was expressed in the posterior primitive heart tube as early as stage 12 and that an additional myosin isoform was expressed in all cardiac myocytes at these early stages of development.¹² Together, these studies demonstrated that diversified populations of cardiac myocytes are established in the primitive heart tube. In contrast, other monoclonal antibody studies hypothesized the presence of a uniform primary myogenic phenotype throughout the newly formed heart that only later becomes diversified with regionalization of the heart and formation of the chambers.^{13 14} Based on these studies, two hypotheses of how cardiac myogenic lineages diverge were formulated: (1) Atrial and ventricular myogenic phenotypes are generated separately at the earliest stages of heart formation with no common differentiated precursor population. (2) The myogenic phenotype of newly differentiated cardiac myocytes is uniform along the length of the primitive heart tube, and diversified phenotypes become apparent after looping and elongation of the primitive heart tube.

Characterization of chamber-specific gene expression based on analysis of mRNA levels was used to test these hypotheses. We have isolated and characterized two cardiac myosin heavy chain isoforms. One, VMHC1, is expressed specifically in the ventricles after day 5 of development but is also expressed throughout the early definitive heart and in the differentiating somites.¹⁵ A second isoform, AMHC1, is atrial specific.⁴ Comparison of the expression patterns of these two genes during heart formation demonstrated that the posterior population of cardiac precursors differentiates with a different phenotype than the anterior progenitors during stages 8 to 11 (Figure, panel B). Specifically, the anterior myocyte population expresses VMHC1 but not AMHC1 when they differentiate, and the posterior segments of the fusing heart express both isoforms. The diversified phenotypes are evident in populations of myocytes that have not yet fused into the primitive heart tube and that are not yet beating. In these studies, no uniform differentiated phenotype was observed along the anteroposterior axis during early heart formation. The expression pattern of VMHC1 throughout the primitive heart tube and then in the ventricles is the same as the primordial myosin expression pattern observed by Sweeney et al in 1987.¹² Studies in mice and zebra fish also demonstrated that diversification of myogenic phenotypes is a feature of the very earliest stages of heart formation. Chamber-specific myosin light chains are expressed differentially along the anteroposterior axis of the forming primitive heart tube of the mouse at days 8 and 9 of development.¹⁶ Additionally, monoclonal antibody studies in the zebra fish detected atrial-specific myosin gene expression in the primitive heart tube.¹⁷ Therefore, diversification of cardiomyogenic lineages appears to occur during the earliest stages of heart formation in a variety of vertebrate species.

	When Are Atrial and Ventricular Lineages Specified?

Top Introduction Where Are Atrial and... When Are Atrial and... When Are Atrial and... What Regulatory Mechanisms Are... Summary References

 
Specification of cell lineages can be defined as the ability to express a certain phenotype in a neutral environment, whereas determination is the ability to differentiate in different cellular environments.¹⁸ Differentiation in studies of myogenesis is defined as the activation of contractile protein gene expression. The events responsible for myogenic lineage specification and determination in the developing heart appear to be based on the position of progenitors within the cardiogenic region. Transplantation studies were used to establish when myogenic lineages are determined in vivo. Posterior cardiac progenitors placed in the anterior heart demonstrated a positional change in myogenic phenotype, as determined by differential beat rates along the anteroposterior axis of the primitive heart tube.¹⁹ In these experiments, transplanted undifferentiated cardiac precursors expressed the phenotype of the neighboring cells in the early heart tube, demonstrating that at these early stages the diversified phenotypes are not stably determined. Transplanted differentiated myocardium maintained its diversified phenotype regardless of position. Therefore, the diversified myogenic phenotypes appear to be determined when they differentiate according to their positions along the anteroposterior axis of the heart-forming region. Specification of cardiomyogenic lineages can be assessed by removing cardiac progenitors from the embryo and allowing them to differentiate in vitro. Studies in which cardiac progenitors were cultured at clonal density in growth factor–rich medium demonstrated that cells removed from the embryo before differentiation (stage 8) expressed chamber-specific myosin heavy chains, as detected by monoclonal antibodies.⁸ Further experiments in which cardiogenic explants were removed as tissue fragments from the embryo at stages soon after gastrulation (stage 4) and up to differentiation (stage 8) and cultured in minimal medium without added growth factors demonstrated that chamber-specific gene expression was activated in a position-dependent manner. The atrial-specific myosin heavy chain gene was expressed only in the posterior cardiac progenitors and not in the anterior progenitors when they differentiated in culture.³

The mechanisms by which cardiomyogenic lineages are diversified have not been characterized. Endoderm has been characterized as playing an inductive role in cardiogenesis in studies that used beating tissue as an end-point assay for myogenic differentiation.²⁰ Recently, however, it has been shown in the chick that anterior endoderm is not necessary for the initiation of cardiac differentiation but is required later, during the terminal phases of differentiation.²¹ The observation that heart progenitors diversify normally in the absence of endoderm indicates that signals emanating from endoderm associated with the heart-forming region are not necessary to maintain positional information or specification of cardiomyogenic lineages.¹⁹ In addition, these in vitro studies demonstrated that organogenesis of the heart is not necessary to maintain these lineages. Once removed from the embryo, the atriogenic and ventriculogenic precursors retain their positional information, as shown by chamber-specific gene expression in a minimal culture system. The observation that position-dependent myosin expression occurs in cardiac precursors removed from the embryo soon after gastrulation supports the hypothesis that positional information is imparted to the anterolateral plate mesoderm at the earliest stages of embryogenesis, perhaps during gastrulation. Fate-mapping studies using vital dyes in zebra fish embryos demonstrated that the atrial and ventricular myogenic lineages appear to separate at the midblastula.¹⁷ Taken together, these studies indicate that diversification is an early event in embryogenesis and that the cardiogenic mesoderm itself is sufficient to maintain distinct myogenic lineages.

	What Regulatory Mechanisms Are Involved in Cardiomyogenic Lineage Diversification?

Top Introduction Where Are Atrial and... When Are Atrial and... When Are Atrial and... What Regulatory Mechanisms Are... Summary References

 
Transplantation and explantation studies have demonstrated that expression of diversified cardiac phenotypes in undifferentiated cardiogenic tissue is positionally dependent. One mechanism by which anteroposterior polarity is established is regional expression patterns of homeoprotein expression. In the limb and central axis, positional information based on homeoprotein expression has been shown to be altered by retinoic acid treatment.^{22 23} The molecular events involved in these morphological changes have not been completely characterized, but retinoic acid response elements have been shown to regulate homeoprotein gene expression directly.²⁴ Although positionally restricted homeoproteins have not been characterized in the primitive heart or cardiogenic precursors, several studies have observed the effects of retinoic acid treatment on heart formation during early embryogenesis. In the chick, the effects of retinoic acid on early heart formation are twofold and distinct. First, retinoic acid inhibits the embryonic folding events that place the cardiac progenitors posteriorly and medially so that fusion of the primordia into the primitive heart tube at the midline is inhibited.^{4 25} Second, retinoic acid treatment of embryos at stages 4 to 8 produces an age- and dose-dependent expansion of atrial-specific gene expression without altering the area of cardiogenic tissue.⁴ Therefore, a posteriorization of diversified cardiac phenotype is produced by retinoic acid treatment before heart differentiation. After differentiation, the atrial gene expression pattern does not change with retinoic acid treatment, again demonstrating that the phenotypes are stable after differentiation. In many cases, the expansion of the atrial phenotype was observed in embryos with a structurally normal primitive heart tube, demonstrating that fusion of the cardiac primordia is not necessary for the respecification of diversified cardiac lineages. To determine whether the retinoic acid–induced posteriorization of the myogenic phenotype is intrinsic to the cardiogenic tissue and is not dependent on embryonic structures, cardiogenic tissue explants were treated with retinoic acid in vitro.¹⁹ In these experiments, anterior cardiac progenitors that were removed from the embryo at stages 5 to 8 converted to the posterior phenotype with retinoic acid treatment in a minimal culture system. After stage 8, the anterior phenotype could not be altered. Therefore, retinoic acid acts on the cardiogenic cells themselves to alter the diversified myogenic phenotype but does not affect commitment to the cardiac lineage at these stages. These studies indicate that stages 5 to 8 provide a window of time during which the diversified state of the cardiogenic precursors can be altered.

Whereas studies of the chicken heart focused on the stages after gastrulation, retinoic acid treatment of gastrulating frog and zebra fish embryos produced a deletion of heart structures.^{26 27} The early loss of cardiac precursors with retinoic acid treatment suggests that an additional effect of retinoic acid may be a prevention of cardiac lineage establishment as it proceeds in an anterior to posterior direction during gastrulation. Therefore, retinoic acid appears to influence at least two events during early cardiogenesis: (1) the commitment of mesoderm to the cardiac lineage around the time of gastrulation and (2) the later diversification of committed cardiogenic cells to distinct anterior and posterior myogenic lineages. To examine the mechanisms by which retinoic acid influences development, several recent reports have described retinoic acid receptor isoform knockout experiments in transgenic mice. In general, the overall body plan and pattern formation of these animals was normal. Although some defects in later events of heart development such as septation and trabeculation were affected in these studies, the early pattern formation and lineage diversification of the heart appeared to be normal.^{28 29 30 31} In most cases, the hearts of the transgenic animals were composed of four identifiable chambers with thin-walled atria and thicker muscular ventricles. Since multiple isoforms of retinoic acid receptors are expressed at the early stages of development, it is possible that the isoforms involved in early heart patterning were not eliminated or that other isoforms compensated for the missing gene expression.

Genes involved in activating or maintaining the diversification of cardiac lineages or anteroposterior positional information in the heart have not been characterized. The ability of retinoic acid to posteriorize the primitive heart tube in the chick is suggestive of a role for homeoproteins in regionalizing the heart tube. A limited number of homeoproteins have been detected in the forming heart. The earliest of these is Csx/Nkx2.5, the vertebrate homologue of the Drosophila gene tinman, which is expressed throughout the cardiogenic region of the mouse during heart formation and is also expressed in the associated pharyngeal endoderm.^{32 33} Since its expression pattern is not regionalized, it is not a good candidate for establishing anteroposterior polarity during early heart development. Other homeoproteins have been associated with valve formation and development of the conduction system at later stages of heart organogenesis but have not been analyzed during the earliest stages of heart formation.³⁴ Ultimately, the identification of chamber-specific regulatory elements in positionally restricted genes and characterization of the transcription factors regulating these genes will be important in understanding the mechanisms underlying diversification of myocyte lineages in the developing heart.

	Summary

Top Introduction Where Are Atrial and... When Are Atrial and... When Are Atrial and... What Regulatory Mechanisms Are... Summary References

 
Recent studies in the chicken, frog, zebra fish, and mouse have examined the origins of diversified myogenic lineages of the heart and the mechanisms by which these lineages are established. These studies have determined that lineage diversification has occurred by the time the heart is forming and that the position of cardiac progenitors along the anteroposterior axis of the embryo is important in the specification of atrial and ventricular precursors. The ability of retinoic acid to alter diversified cardiac phenotypes suggests that positional information may play a determinative role in myocyte lineage diversification. The mechanism by which these changes in cell fate occur has yet to be determined. Experiments with undifferentiated precardiac cells demonstrated that tissue removed from the embryo exhibits positionally restricted gene expression when removed soon after gastrulation. Therefore, diversified lineage specification may occur during gastrulation or during migration of precardiac cells to the anterolateral plate mesoderm. In addition, organogenesis of the heart and exposure to cells or factors outside the heart-forming region are not necessary to maintain diversified cardiac lineages. Further studies are necessary to determine how the heart lineage is established during early development and whether diversification of the myocytes occurs concomitantly. Thus, although much progress has been made in characterizing the timing and tissue restrictions of lineage-diversification events, the molecular affectors and initial agents involved in myocyte lineage determination have yet to be identified.

	Acknowledgments

 
This study was funded by National Institutes of Health (NIH) grants HL-34318 and HL-37675 to Dr Baker and NIH postdoctoral fellowship HL-08914 to Dr Yutzey. We are grateful to M. Gannon for preparation of art work, and we thank M. Gannon and Dr A. Valder for valuable discussions.

Received February 16, 1995; accepted May 3, 1995.

	References

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