© 2000 American Heart Association, Inc.
Editorial |
Whither Complexity in Myocardial Development?
From the Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Ga.
Correspondence to Margaret L. Kirby, PhD, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912-2640. E-mail mkirby{at}mail.mcg.edu
Key Words: myocardium • development • gene expression • domains
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Introduction |
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 Top Introduction References |
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For anyone who has ever been on the sidelines during a discussion of congenital heart defects or had a few minutes to browse through Bharati and Lev’s 2-volume tome on heart malformations,1 the complexity of cardiovascular development that underlies this pathology is painfully obvious. Our understanding of heart development in particular has lagged behind that of other more tidily developing organs that have the leisure of putting themselves together before they have to do anything. Perhaps it is for these reasons that the molecular age has come to heart development a bit slower and more painstakingly than to other systems.
The initial foray into heart development at the molecular level came from cell biologists, who had developed sophisticated reagents to study skeletal muscle contractile proteins and looked to the myocardium as another striated muscle. Gonzalez-Sanchez and Bader2 developed the first antibodies that detected differences in myosin heavy chains in the developing chick heart. One antibody, MF20, is now used as a pan-myocardial marker in chick, and another was the first to specifically recognize only atrial myosin heavy chains. The same group quickly identified another myosin heavy chain that characterized the embryonic conduction system.3 This confirmed conventional wisdom from morphologists, who saw 3 types of myocardia: atrial, ventricular, and conduction (Purkinje). It additionally showed that differential expression of contractile protein isoforms occurred relatively early in development, well before the morphologists could see any differences. The regions of differential expression seemed rather flexible at first and could be altered epigenetically by agents like retinoic acid.4
It was also recognized that the outflow myocardium
maintained expression of 
smooth muscle actin long after the rest of
the myocardium stopped synthesizing it in
chick.5 But myocardial
differences are not limited to contractile protein expression. The
outflow and atrioventricular myocardium were known to have the ability
to induce epithelial-to-mesenchymal transformation of the endocardium
to form cushion mesenchyme in both chick and
mouse,6 7 whereas
the other regions of the myocardium lack this capacity, additionally
supporting the idea that the myocardium of the heart tube is not
homogeneous but is partitioned into segments. Thus, by about the mid
1990s, the data were in place to make the general observation that the
myocardium of the primary heart tube was segmented. The segments were
defined as inflow tract, embryonic atria, atrioventricular canal,
embryonic ventricle, and outflow tract. The discovery that e-HAND and
d-HAND expression were restricted to the left and right ventricular
primordia in mouse8 enhanced
the impression that genes expressed early in myocardial development
might have some predictive value. I could go on with examples to avoid
slighting hundreds of excellent studies on this subject, but you have
the general idea. Although it is out-of-date only 2 years after being
published, a 1998 review by Franco et
al9 lists 51 differentially
expressed genes in the developing myocardium at 4 generally recognized
stages of heart development: precardiac mesoderm, primary tube stage,
looped or segmented stage, and fetal or septated stage. Although the
genes on this list span the gamut of functions in the myocardium, they
are certainly not exhaustive.
To assist in its complicated twisting and repositioning of segments, the primary heart tube must carry distinct axial information so that connections can be established properly with the independently developing vasculature of the rest of the body. For example, any misstep in interpreting left-right axial information can lead to mild congenital variants, such as persistent left superior vena cava, moderate defects, such as partial or total anomalous return of the great veins to the atria, or severely abnormal sequences of congenital malformations, such as atriovisceral heterotaxy.
Although we understand little about the left-right axis in the heart, it played a prominent role in the early studies of left-right axis determinants, because by looping to the right, the heart is the first organ to break the bilateral symmetry of early development. Thus, the end point of many left-right studies from zebrafish, frog, chick, and mouse has been left, right, or ambiguous heart loops. Most of the genes that we now recognize as left-right axis genes are actually expressed on the left. Nodal, lefty, and Pitx210 11 12 13 14 are genes that are induced in the left lateral plate mesoderm. Both nodal and lefty can induce the expression of Pitx2, which seems to act as one of the executors of left-right patterning.15 Mouse embryos that are homozygous for a null allele of Pitx2 have a single atrium among other defects.16 17 18
In an attempt to understand how gene expression is related functionally to cardiac morphogenesis and particularly to development of the conduction system, a group based in Amsterdam and led by Antoon Moorman19 has been very active in defining different myocardial expression domains. In their most recent study, published in this issue of Circulation Research, Franco et al20 propose that there are at least 4 different transcriptional domains in the inflow and atrial compartments of the looped heart tube. The 4 compartments are delimited using the expression patterns of atrial natriuretic factor, myosin light chain 2V, and Pitx2, combined with data from transgenic mouse lines expressing lacZ under the control of regulatory sequences of a mouse myosin light chain (1F/3F). Because of the involvement of Pitx2, which is expressed in the left heart field, the compartments are parceled into left and right. The 4 domains they propose are atrioventricular canal myocardium, which will be incorporated into the base of the fetal atria; the atrial appendages, which are formed from the embryonic atria; the myocardium around the caval veins, which is continuous with the left and right venous valve leaflets in the wall of the right atrium; and myocardium associated with the pulmonary vein, which includes the primary and secondary atrial septa (see Figure 8 of Franco et al20 ).
How is this new cataloging of expression domains, which is admittedly phenomenological, helpful in understanding the development of the heart? Kelly et al21 refer to the expression domains in the myocardium as cardiosensors, which they believe can be used in the analysis of both normal and abnormal heart development. In support of this idea, the Holt-Oram syndrome, which is characterized by a secundum-type atrial septal defect (involving the ostium secundum in the primary atrial septum) and ventricular septal defect combined with anomalies of the upper limb, is associated with mutations in Tbx5.22 23 TBX5 protein distribution is consistent with anatomic distribution of human Holt-Oram syndrome cardiac defects in that atrial TBX5 expression is greater than ventricular expression bilaterally.24 25 We also know that TBX5 can affect myocardial development, because retinoic acid treatment of chick embryos causes altered TBX5 expression along with changes of the embryonic ventricular myocardium consistent with atrialization.26 However, the expression domain–developmental defect correlation is lost at this point, because we do not understand the significance of graded TBX5 expression within the myocardium of the left-sided chambers with the most prominent expression in subepicardial myocytes.25
Certainly, one of the most important observations in the study by Franco et al20 is differential gene expression in the systemic and pulmonary connections to the right and left atrial walls. This is not the first study to show differential gene expression in the atria. Wessels et al27 found the expression of creatine kinase B to be consistently higher in the left atrial myocardium than in the right, with a sharp boundary between high and low expression located between the primary septum and left venous valve leaflet in the developing human heart, reminiscent of the expression of Pitx2.18 20 The site of pulmonary vein formation is still a subject of controversy, but these data suggest that it shares its origin with that of the atrial septum, and because of the expression of Pitx2 in this domain, both are initially left-sided structures. Atrial septal defects usually accompany partial anomalous pulmonary venous connection, and total anomalous pulmonary venous connection with right atrial isomerization (both atria appear to be right-sided) occurs with particularly high frequency in asplenia.28 However, the fact that only 9% of patients with atrial septal defect have partial anomalous pulmonary venous connection29 suggests that the story of expression domains is really more complicated than the present proposal by Franco et al20 or that expression domains do not explain these defects.
So far, despite the thousands of research hours spent mapping gene expression in the developing heart, most of the linkages of genes with congenital heart defects have been first identified in children with cardiac disease, with subsequent description of the developmental expression pattern of the mutant gene. Where does this leave us? What can we learn from expression domains in the heart other than how complex heart development really is? Are these domains meaningful functional domains that indicate cell lineage? It is still too early to know for sure, because the data do not entirely support a connection between myocardial compartments on the basis of gene expression and either subsequent normal development or production of specific malformations. My guess is that we still lack some of the key pieces of information, but that still does not lessen the potential power of the observations by Franco et al,20 because, after all, it is only possible to tackle big problems one step at a time.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Bharati S, Lev M. The Pathology of Congenital Heart Disease: A Personal Experience With More Than 6,300 Congenitally Malformed Hearts. Armonk, NY: Futura; 1996.
2. Gonzalez-Sanchez A, Bader D. Immunochemical analysis of myosin heavy chains in the developing chicken heart. Dev Biol. 1984;103:151–158.[Medline] [Order article via Infotrieve]
3. Zadeh BJ, Gonzalez-Sanchez A, Fischman DA, Bader DM. Myosin heavy chain expression in embryonic cardiac cell cultures. Dev Biol. 1986;115:204–214.[Medline] [Order article via Infotrieve]
4. Yutzey KE, Rhee JT, Bader D. Expression of the atrial-specific myosin heavy chain AMHC1 and the establishment of anteroposterior polarity in the developing chicken heart. Development. 1994;120:871–883.[Abstract]
5.
Ruzicka DL,
Schwartz RJ. Sequential activation of alpha-actin genes during avian
cardiogenesis: vascular smooth muscle -actin gene transcripts mark
the onset of cardiomyocyte differentiation.
J Cell Biol. 1988;107:2575–2586.
6. Mjaatvedt CH, Lepera RC, Markwald RR. Myocardial specificity for initiating endothelial-mesenchymal cell transition in embryonic chick heart correlates with a particulate distribution of fibronectin. Dev Biol. 1987;119:59–67.[Medline] [Order article via Infotrieve]
7.
Nakajima Y,
Miyazono K, Kato M, Takase M, Yamagishi T, Nakamura H. Extracellular
fibrillar structure of latent TGF ß binding protein-1: role in TGF
ß-dependent endothelial-mesenchymal transformation during endocardial
cushion tissue formation in mouse embryonic heart.
J Cell Biol. 1997;136:193–204.
8. Srivastava D, Cserjesi P, Olson EN. A subclass of bHLH proteins required for cardiac morphogenesis. Science. 270:1995–1999.
9.
Franco D, Lamers
WH, Moorman AFM. Patterns of expression in the developing myocardium:
towards a morphologically integrated transcriptional model.
Cardiovasc Res. 1998;38:25–53.
10. St Amand TR, Ra J, Zhang Y, Hu Y, Baber SI, Qiu M, Chen Y. Cloning and expression pattern of chicken Pitx2: a new component in the SHH signaling pathway controlling embryonic heart looping. Biochem Biophys Res Commun. 1998;247:100–105.[Medline] [Order article via Infotrieve]
11. Yoshioka H, Meno C, Koshiba K, Sugihara M, Itoh H, Ishimaru Y, Inoue T, Ohuchi H, Semina EV, Murray JC, Hamada H, Noji S. Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry. Cell. 1998;94:299–305.[Medline] [Order article via Infotrieve]
12. Ryan AK, Blumberg B, Rodriguez-Esteban C, Yonei-Tamura S, Tamura K, Tsukui T, de la Pena J, Sabbagh W, Greenwald J, Choe S, Norris DP, Robertson EJ, Evans RM, Rosenfeld MG, Izpisua Belmonte JC. Pitx2 determines left-right asymmetry of internal organs in vertebrates. Nature. 1998;394:545–551.[Medline] [Order article via Infotrieve]
13. Piedra ME, Icardo JM, Albajar M, Rodriguez-Rey JC, Ros MA. Pitx2 participates in the late phase of the pathway controlling left-right asymmetry. Cell. 1998;94:319–324.[Medline] [Order article via Infotrieve]
14. Logan M, Pagan-Westphal SM, Smith DM, Paganessi L, Tabin CJ. The transcription factor Pitx2 mediates situs-specific morphogenesis in response to left-right asymmetric signals. Cell. 1998;94:307–317.[Medline] [Order article via Infotrieve]
15.
Burdine RD,
Schier AF. Conserved and divergent mechanisms in left-right axis
formation. Genes Dev. 2000;14:763–776.
16. Gage PJ, Suh H, Camper SA. Dosage requirement of Pitx2 for development of multiple organs. Development. 1999;126:4643–4651.[Abstract]
17. Lu MF, Pressman C, Dyer R, Johnson RL, Martin JF. Function of Rieger syndrome gene in left-right asymmetry and craniofacial development. Nature. 1999;401:276–278.[Medline] [Order article via Infotrieve]
18. Kitamura K, Miura H, Miyagawa-Tomita S, Yanazawa M, Katoh-Fukui Y, Suzuki R, Ohuchi H, Suehiro A, Motegi Y, Nakahara Y, Kondo S, Yokoyama M. Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra- and periocular mesoderm and right pulmonary isomerism. Development. 1999;126:5749–5758.[Abstract]
19.
Moorman AFM, de
Jon F, Denyn MMFJ, Lamers WH. Development of the cardiac conduction
system. Circ Res. 1998;82:629–644.
20.
Franco D,
Campione M, Kelly R, Zammit PS, Buckingham M, Lamers WH, Moorman AFM.
Multiple transcriptional domains, with distinct left and right
components, in the atrial chambers of the developing heart.
Circ Res. 2000;87:984-991.
21. Kelly RG, Zammit PS, Buckingham ME. Cardiosensor mice and transcriptional subdomains of the vertebrate heart. Trends Cardiovasc Med. 1999;9:3–10.[Medline] [Order article via Infotrieve]
22. Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD. Holt-Oram syndrome is caused by mutations in TBX5, a memer of the Brachyuiry (T) gene family. Nat Genet. 1997;15:21–29.[Medline] [Order article via Infotrieve]
23. Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet. 1997;15:30–35.[Medline] [Order article via Infotrieve]
24. Bruneau BG, Logan M, Davis N, Levi T, Tabin CJ, Seidman JG, Seidman CE. Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. Dev Biol. 1999;211:100–108.[Medline] [Order article via Infotrieve]
25. Hatcher CJ, Goldstein MM, Mah CS, Delia CS, Basson CT. Identification and localization of TBX5 transcription factor during human cardiac morphogenesis. Dev Dyn. 2000;219:90–95.[Medline] [Order article via Infotrieve]
26. Liberatore CM, Searcy-Schrick RD, Yutzey KE. Ventricular expression of tbx5 inhibits normal heart chamber development. Dev Biol. 2000;223:169–180.[Medline] [Order article via Infotrieve]
27. Wessels A, Anderson RH, Markwald RR, Webb S, Brown NA, Viragh S, Moorman AFM, Lamers WH. Atrial development in the human heart: an immunohistochemical study with emphasis on the role of mesenchymal tissues. Anat Rec. 2000;259:288–300.[Medline] [Order article via Infotrieve]
28. Lucas RV Jr. Anomalous venous connections, pulmonary and systemic. In: Adams FH, Emmanouilides GC, eds. Moss’ Heart Disease in Infants, Children, and Adolescents. 3rd ed. Baltimore, Md: Williams & Wilkins; 1983:458–491.
29. Gotsman MS, Astley R, Parsons C. Partial anomalous pulmonary venous drainage in association with atrial septal defect. Br Heart J. 1965; 27:566. Cited by: Lucas RV Jr. Anomalous venous connections, pulmonary and systemic. In: Adams FH, Emmanouilides GC, eds. Moss’ Heart Disease in Infants, Children, and Adolescents. 3rd ed. Baltimore, Md: Williams & Wilkins; 1983:458.
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