The heart is one of the earliest differentiating and functioning organs. It develops from cardiogenic mesoderm that originally lies above the cranial end of the developing neural tube. Enlargement of the cranial neural fold brings this region ventrally to its correct anatomical position. The original paired cardiac tubes fuse, with the "ventricular" primordia initially lying above the "atria". Growth of the cardiac tube flexes it into an "S-shape" tube, rotating the "ventricles" downward and pushing the "atria" upward.
The Human Heart from day 10 to 25 (More? Carnegie Stages - SEM Image: K Sulik)
The complete molecular mechanisms regulating cardiac development are still largely unknown. Development does appear to be an independent mechanism preceding both skeletal and smooth muscle development and using different regulatory mechanisms (not MyoD or myogenin). (More? see Muscle molecular development)
This page also includes some information on molecular regulation of blood vessel formation (More? Blood Vessels).
Specific programs of gene expression for (cell specification, differentiation, growth, and migration) appear regulated by multiple transcription factors and signaling pathways. So far the transcription factors Nkx2-5, GATA-4, eHAND, dHAND, Irx4, and Tbx5 and the Wnt/beta-catenin signaling pathway have been implicated as playing important roles in cardiac development.
Page Links: Introduction | Some Recent Findings | Pathways | Hand1 | Wnt/Beta-Catenin Signaling | Bone Morphogenetic Proteins | Akt/PKB Signaling | Tbx5 Signaling | Vascular Endothelial Growth Factor | Notch | Jagged1 | Myocardin | Objectives | Learning activities | Development Overview | Blood flow through the Embryo | Pig Overview | Terms | References | Use the lefthand menu Internal Links to view other cardiovascular pages |
Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Chen MJ, Yokomizo T, Zeigler BM, Dzierzak E, Speck NA. Nature. 2009 Jan 7.
"It is thought that HSCs emerge from vascular endothelial cells through the formation of intra-arterial clusters and that Runx1 functions during the transition from 'haemogenic endothelium' to Haematopoietic stem cells (HSCs). ...Collectively these data show that Runx1 function is essential in endothelial cells for haematopoietic progenitor and HSC formation from the vasculature, but its requirement ends once or before Vav is expressed."
Sultana N, Nag K, Hoshijima K, Laird DW, Kawakami A, Hirose S. Zebrafish early cardiac connexin, Cx36.7/Ecx, regulates myofibril orientation and heart morphogenesis by establishing Nkx2.5 expression. Proc Natl Acad Sci U S A. 2008 Mar 12;
"...propose that the cardiac connexin Ecx and its downstream signaling are crucial for establishing nkx2.5 expression, which in turn promotes unidirectional, parallel alignment of myofibrils and the subsequent proper heart morphogenesis."
High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA. Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci U S A. 2008 Feb 1;
"The Notch ligand Jagged1 (Jag1) is essential for vascular remodeling. ...Jag1 null phenotype. These embryos show striking deficits in vascular smooth muscle, whereas endothelial Notch activation and arterial-venous differentiation appear normal."
Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 2007 Feb 15;445(7129):776-80.
"In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A. ...suggest that Dll4-Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns."
Naito AT, Shiojima I, Akazawa H, Hidaka K, Morisaki T, Kikuchi A, Komuro I. Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19812-7.
"Wnt/beta-catenin signaling exhibits biphasic and antagonistic effects on cardiomyogenesis and hematopoiesis/vasculogenesis, depending on the stage of development." (More? Wnt/Beta-Catenin Signaling)
Creemers EE, Sutherland LB, McAnally J, Richardson JA, Olson EN. Myocardin is a direct transcriptional target of Mef2, Tead and Foxo proteins during cardiovascular development. Development. 2006 Oct 4.
"Myocardin is a transcriptional co-activator of serum response factor (Srf), which is a key regulator of the expression of smooth and cardiac muscle genes. Consistent with its role in regulating cardiovascular development, myocardin is the earliest known marker specific to both the cardiac and smooth muscle lineages during embryogenesis."
Xin M, Davis CA, Molkentin JD, Lien CL, Duncan SA, Richardson JA, Olson EN. A threshold of GATA4 and GATA6 expression is required for cardiovascular development. Proc Natl Acad Sci U S A. 2006 Jul 17;
Pathways below are organsied such that you start at the top and read downwards in each column (there is no relationship shown between columns) and some data is still controversial.
|
Heart |
Smooth Muscle | Blood Vessels | |
Cx36.7/Ecx |
Mef2, Tead and Foxo | Jagged1 | Dll4-Notch1 | |
| Nkx2.5 | Myocardin (early marker specific to cardiac and smooth muscle lineages) | Notch | ||
Reviews
Wherefore heart thou? Embryonic origins of cardiogenic mesoderm
The anterior heart-forming field: voyage to the arterial pole of the heart
Bruneau BG. Transcriptional regulation of vertebrate cardiac morphogenesis Circ Res. 2002 Mar 22;90(5):509-19.
Articles
Naito AT, Shiojima I, Akazawa H, Hidaka K, Morisaki T, Kikuchi A, Komuro I. Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19812-7.
Creemers EE, Sutherland LB, McAnally J, Richardson JA, Olson EN. Myocardin is a direct transcriptional target of Mef2, Tead and Foxo proteins during cardiovascular development. Development. 2006 Oct 4. myocardin protein that acts as a transcriptional co-activator of serum response factor (Srf) a regulator of smooth and cardiac muscle gene expression.
Yutzey KE, Kirby ML. Wherefore heart thou? Embryonic origins of cardiogenic mesoderm. Dev Dyn. 2002 Mar;223(3):307-20. Review.
Srivastava, D., and Olson, E.N. (2000). A genetic blueprint for cardiac development. Nature 407, 221&endash;226.
Srivastava, D., Thomas, T., Lin, Q., Kirby, M.L., Brown, D., and Olson, E.N. (1997). Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nat. Genet.16, 154&endash;160.
Bruneau etal., (2001) A Murine Model of Holt-Oram Syndrome Defines Roles of the T-Box Transcription Factor Tbx5 in Cardiogenesis and Disease Cell, Vol. 106, 709&endash;721.
Search PubMed
Search Jan2007 "molecular heart development" 4,611 reference articles of which 1,047 were reviews.
Search PubMed: term= molecular heart development
VEGF Models (spacefill and worms, Image: MMDB)
Growing blood vessels follow a gradient generated by tagret tissues/regions of Vascular Endothelial Growth Factor (VEGF) to establish a vascular bed. Recent findings suggest that Notch signaling acts as an inhibitor for this system, preventing sprouting of blood vessels.
Notch is a transmembrane receptor protein involved in regulating cell differentiation in many developing systems.
Jagged 1 activation of the Notch receptor leads to cleavage of the intracellular part of the Notch receptor from the membrane which translocates to the nucleus and activate s transcription factors.
Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 2007 Feb 15;445(7129):776-80.
"In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A. ...suggest that Dll4-Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns."
Links: OMIM - VEGFA | OMIM - Notch
Hand1 gene (also called Hxt, eHAND, Thing1) encodes a basic helix-loop-helix (bHLH) transcription factor needed for both placenta (trophoblast) and cardiac development (mouse). A knockout study showed abnormal looping and ventricular myocardial differentiation. (Riley etal, 1998)
Srivastava, D., Thomas, T., Lin, Q., Kirby, M.L., Brown, D., and Olson, E.N. (1997). Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nat. Genet.16, 154&endash;160.
The Wnt/Beta-Catenin signaling pathway is utilised by several different developing systems including the heart. A recent paper has identified several key roles for this signaling pathway in cardiogenesis and these roles change during the timecourse of heart development.
Naito AT, Shiojima I, Akazawa H, Hidaka K, Morisaki T, Kikuchi A, Komuro I. Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19812-7.
"Wg/armadillo signaling promotes heart development in Drosophila, whereas activation of Wnt/beta-catenin signaling inhibits heart formation in avians and amphibians. Using an in vitro system of mouse ES cell differentiation into cardiomyocytes, we show here that Wnt/beta-catenin signaling exhibits developmental stage-specific, biphasic, and antagonistic effects on cardiomyogenesis and hematopoiesis/vasculogenesis. Activation of the Wnt/beta-catenin pathway in the early phase during embryoid body (EB) formation enhances ES cell differentiation into cardiomyocytes while suppressing the differentiation into hematopoietic and vascular cell lineages. In contrast, activation of Wnt/beta-catenin signaling in the late phase after EB formation inhibits cardiomyocyte differentiation and enhances the expression of hematopoietic/vascular marker genes through suppression of bone morphogenetic protein signaling. Thus, Wnt/beta-catenin signaling exhibits biphasic and antagonistic effects on cardiomyogenesis and hematopoiesis/vasculogenesis, depending on the stage of development."
Bone morphogenetic proteins (BMPs) are growth factors belonging to the transforming growth factor beta (TGFbeta) superfamily. These proteins have many different roles in different tissues and bind cell surface receptor kinases to activate intracellular (downstream) Smad proteins which then act as transcription factors within cells.
van Wijk B, Moorman AF, van den Hoff MJ. Role of bone morphogenetic proteins in cardiac differentiation. Cardiovasc Res. 2006 Nov 21
"This review summarizes the effects of BMP and the signaling pathways that regulate the differentiation of cardiomyocytes from mesoderm in the heart-forming region and at the distal borders of the heart tube from the second heart field. Subsequently, the role of BMPs in the formation of the ventricular chambers and septovalvulogenesis in the atrioventricular canal and outflow tract is described. Finally, the effects of BMPs in stem cell biology and cardiac regeneration are discussed."
Role in endocardial cushion formation
Gaussin et al., Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3PNAS 2002;99 2878-2883
"Receptors for bone morphogenetic proteins (BMPs), members of the transforming growth factor- (TGF) superfamily, are persistently expressed during cardiac development, yet mice lacking type II or type IA BMP receptors die at gastrulation and cannot be used to assess potential later roles in creation of the heart. Here, we used a Cre/lox system for cardiac myocyte-specific deletion of the type IA BMP receptor, ALK3. ALK3 was specifically required at mid-gestation for normal development of the trabeculae, compact myocardium, interventricular septum, and endocardial cushion. Cardiac muscle lacking ALK3 was specifically deficient in expressing TGF2, an established paracrine mediator of cushion morphogenesis. Hence, ALK3 is essential, beyond just the egg cylinder stage, for myocyte-dependent functions and signals in cardiac organogenesis."
The heart continues to grow postnatally mainly by hypertrophy of existing myocytes rather than proliferation of cardiomyocytes. The Akt/PKB (a serine/threonine protein kinase) signaling pathway has been implicated as having a role in postnatal growth and other normal/abnormal cardiogenic growth mechanisms.
Shiojima I, Walsh K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev. 2006 Dec 15;20(24):3347-65.
"The serine/threonine protein kinase Akt is activated by various extracellular stimuli in a phosphatidylinositol-3 kinase-dependent manner and regulates multiple aspects of cellular functions including survival, growth and metabolism. In this review we will discuss the role of the Akt signaling pathway in the heart, focusing on the regulation of cardiac growth, contractile function, and coronary angiogenesis."
Tbx5 is a T-box-containing transcription factor which, like other T-box family members, has been implicated in vertebrate tissue patterning and differentiation (Papaioannou and Silver, 1998). A role for Tbx5 in cardiac morphogenesis has been surmised from its expression pattern (Bruneau et al., 1999; Chapman et al., 1996) and from studies of Holt-Oram syndrome (OMIM #142900), a rare autosomal dominant human disease caused by TBX5 mutations (Basson et al., 1997, 1999; Li et al., 1997). Holt-Oram syndrome patients invariably exhibit upper limb malformations and have a high incidence ( 85%) of congenital heart disease. (text modifed from Bruneau etal., (2001) A Murine Model of Holt-Oram Syndrome Defines Roles of the T-Box Transcription Factor Tbx5 in Cardiogenesis and Disease Cell, Vol. 106, 709-721.)
(More? Molecular development Tbx)
Myocardin is a protein that acts as a transcriptional co-activator of serum response factor (Srf) a regulator of smooth and cardiac muscle gene expression.
Creemers EE, Sutherland LB, McAnally J, Richardson JA, Olson EN. Myocardin is a direct transcriptional target of Mef2, Tead and Foxo proteins during cardiovascular development. Development. 2006 Oct 4)
Warkman AS, Yatskievych TA, Hardy KM, Krieg PA, Antin PB. Myocardin expression during avian embryonic heart development requires the endoderm but is independent of BMP signaling. Dev Dyn. 2008 Jan;237(1):216-21.
Maternal Blood | -> umbilical vein -> liver -> anastomosis -> sinus venosus -> atria ventricles-> truncus arteriosus -> aortic sac -> aortic arches-> dorsal aorta-> pair of umbilical arteries | Maternal Blood
This is shown on the stage 13/14 pig G6 section.
Transverse section- Heart is 2 tubes that fuse in the midline anterior to pharynx.
The pericardial cavity can be imagined as the top of the "horseshoe" of the intraembryonic coelom. (where the arms become the pleural cavity and the ends fuse anteriorly to form a single peritoneal cavity).
This view shows the initial positioning of the ventricles above the atria. The ventricles are rotated into their correct anatomical position by the growth of the heart tube, bending into an "S" shape.
Initially...
Cardiac inflow- at the bottom (sinus venosus)
Cardiac outflow- at the top (truncus arteriosus)
Person AD, Klewer SE, Runyan RB. Cell biology of cardiac cushion development. Int Rev Cytol. 2005;243:287-335. Review.
Selected Lists of References from PubMed March 1999 search results are available for School of Anatomy computers without internet access. Computers with internet access can search from either Page 2 or PubMed Internet Access
Click on the listed keywords below (used to search the external database) the most current references on Medline will be displayed.
A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Old Glossary
Page 2 | Abnormalities
| OMIM
| Questions
| Medline
Page
3 | Pig
Stage 13/14
Page
4 | Human
(Stage22) | Selected
Human highpower
Molecular
| Blood
| Text only
page | WWW Links
Heart Movies
Postnatal
Home Page
Embryo stages
Fetal Dev
System Notes
Animal Dev
Acknowledgements
Introduction
Abnormalities
Stage 13/14
Stage 22
Stage 22 Selected Highpower
Heart
Heart Rate
Blood
Blood Vessels
Molecular
Text only page
WWW Links
Heart Movies
Postnatal
Movies
Audio
Class Notes
Serial Images
K12 Students
Abnormal
Prenatal Diagnosis
Animal Embryos
Mechanisms
Molecular
Histology
Statistics
History
Site Map
Glossary
OMIM
School of Med Sci
UNSW Medicine
University of NSW
UNSW Cell Biology
NCBI Books
New 2010 Site
Enjoyed this site? Visit the New 2010 Site!
In human embryos the heart begins to beat at about 22-23 days, with blood flow beginning in the 4th week. The heart is therefore one of the earliest differentiating and functioning organs.
For more general information see Molecular Notes and Factor Notes.
Most texts will separate heart development from vascular development in order to simplify their descriptions of cardiovascular development, though the 2 are functionally and embryologically connected (More? see recent review article).
The heart develops from cardiogenic mesoderm that originally lies above the cranial end of the developing neural tube. Enlargement of the cranial neural fold brings this region ventrally to its correct anatomical position. The original paired cardiac tubes fuse, with the "ventricular" primordia initially lying above the "atria". Growth of the cardiac tube flexes it into an "S-shape" tube, rotating the "ventricles" downward and pushing the "atria" upward. This is then followed by septation, a complex process which converts this simple tube into a four chambered heart. A key part of this process is the separation of cardiac outflow (truncus arteriosus) into a separate pulmonary and aortic arch outflow. During embryonic development there is extensive remodelling of the initially r/l symetrical cardiovascular system and a contribution from the neural crest to some vessels.
As the embryonic/fetal circulation is different to the neonatal circulation (lung/pulmonary activation), several defects of heart septation may only become apparent on this transition. One septal "defect" occurs in us all, the foramen ovale (between the 2 atria) which in general closes in the neonate over time.
The complexity of septation, cardiac outflow separation, remodelling of the peripheral vasculature, and the pre- to post-natal changes may also contribute to the relatively large proportion of birth defects associated with this system.
The molecular mechanisms regulating cardiac development are still largely unknown. Development does appear to be an independent mechanism preceding both skeletal and smooth muscle development and using different regulatory mechanisms (not MyoD or myogenin).
These Notes are currently being updated for Version 4.0
Please email Dr Mark Hill if you wish to make a comment about this current project.