Heart embryo development
Cardiac crescent
Linear heart tube
Looping heart
Chamber formation
Cardiac crescent
In higher vertebrates, heart formation is a complex
process that starts at early stages of embryogenesis,
prior to the end of gastrulation, with commitment of anterior
lateral plate mesoderm cells to the cardiogenic lineage and
their migration and organization into the cardiac crescent.
Commitment to a cardiac fate is the result of inductive signaals from the underlying endoderm, which include :Bone morphogenetic proteins (BMPs)
Basic fibroblast growth factors
Wnt proteins
After aligning into a cardiogenic crescent (~Day 20 in the human embryo), the precardiac cells differentiate and assemble as the bilateral heart tubes (24, 67). At this time, vasculogenesis is also taking place (65) as the formation of the vasculature is tightly correlated with heart development
Looping heart
As development proceeds, the primitive heart tube undergoes a series of complex events, which include chamber specification, septation, and trabeculation, to form the definitive four-chambered heart (Fig. 1). Defects in compartmentalization and proper communication between the four chambers account for the majority of human congenital heart defect (CHD; discussed below). Although the molecular mechanisms underlying cardiac morphogenesis remain largely unknaown, the production of mice in which specific genes were inactivated (“knockouts”) has allowed the identification of proteins involved in chamber maturation and heart morphogenesis (Table 1). Chamber specification is a very early event since the beating heart tube is organized with an anteroposterior polarity anad specific segments are already fated to become, from anterior to posterior, the aortic sac, the conotruncus, the right ventricle, the left ventricle, the atria, and the sinus venosus of the mature heart (Fig. 1). Thus, subtle alterations in early myocyte differentiation could lead to defects in cardiac looping, septation, and compartmentalization. The mechanisms controlling heart tube regionalization are not fully understood.
Chamber formation
In addition to heart-tube-derived myocytes, the mature
heart contains myocytes derived from a distinct heart field,
located in the pharyngeal mesoderm and referred to as the
secondary or anterior heart field (AHF) [30]. Cells from the
AHF are incorporated in the growing heart tube during
the looping stage at the venous and arterial poles. Recently, it
was shown that the myocardium of the right ventricle is
derived from the AHF, further underlining the differences
between the two ventricular compartments [31,32]. The fact
that myocardial cells appear to derive from two embryological
distinct mesodermal lineages is important in understanding
the molecular basis of diseases that differentially
affect the left or right ventricles.
The subsequent stages involve a series of complex steps during which the tubular heart is transformed into a multichambered organ
Factors:
GATA-4
NKX 2.5
TBX 5
HAND 1
HAND 2
GATA-4
nevertheless, transcription
factor (TF) GATA-4, initially identified as one of the key TFs
required for expression of the cardiac natriuretic peptide
genes NPPA and NPPB, is emerging as the critical regulator
of the earliest stages of cardiogenesis. First, GATA-4 is the
competence factor required to allow cells to respond to
cardioinductive substances [1,2], and its combined action
with another TF, Nkx2.5, mediates BMP signaling [3].
During in vitro cardiogenesis, GATA-4 expression precedes
that of Nkx2.5 and several other cardiac regulators and is
essential for survival of cardioblasts [4]. GATA-4 acts
synergistically with the SMAD proteins, the intracellular
effectors of the TGF/BMP signaling pathway to activate
Nkx2.5 transcription [5]. Ectopic GATA-4 expression is
sufficient to induce cardiogenesis in ES cells and in Xenopus
embryonic ectoderm [6]. GATA-4 cardiogenic activity
reflects its activation of cardiogenic growth factors like
BMP-4 [7] as well as other TFs required for heart formation
[8,9]. Thus, GATA-4 is a central player of a self-reinforcing
feedback loop at the onset of cardiogenesis.
NKX 2.5
Although Nkx2.5 is expressed
uniformly throughout the heart, detailed analyses of a
null mutation of Nkx2.5 in mice suggest that Nkx2.5 is
required for proper chamber specification. In human,
mutations in Nkx2.5 are associated with septal and
conduction defects
TBX 5
Another TF, Tbx5, a member of the growing family of
T-box factors, is essential for atrial formation, as evidenced
by the phenotype of null Tbx5 mice [14]. Tbx5 is the gene
mutated in Holt–Oram syndrome (HOS), an autosomal
dominant disease affecting heart and limb development.
Interestingly, mice with heterozygous deletion of Tbx5
recapitulate the full spectrum of HOS
HAND 1 & HAND 2
In addition, two
basic helix–loop–helix TFs, Hand1 and Hand2, which are
expressed in the precardiac mesoderm as well as in
noncardiac precursor cells, have been associated with right and left ventricular specification. Hand2 is expressed
throughout the straight heart tube but becomes restricted to
the future right ventricle during looping, while Hand1 is
restricted to the anterior and posterior regions of the heart
tube, which are fated to become the conotruncus and left
ventricle, respectively. Inactivation of the Hand2 gene in
mice results in embryonic lethality at the looping stage and
the segment of the heart tube destined to form the right
ventricle is absent [15]. Loss of Hand1 results in even earlier
embryonic lethality due to placentation defects, but chimeric
analysis (that rescues the placentation defect) suggests that
Hand1 is required to ensure proper cardiac looping
Cardiac crescent
Linear heart tube
Looping heart
Chamber formation
Cardiac crescent
In higher vertebrates, heart formation is a complex
process that starts at early stages of embryogenesis,
prior to the end of gastrulation, with commitment of anterior
lateral plate mesoderm cells to the cardiogenic lineage and
their migration and organization into the cardiac crescent.
Commitment to a cardiac fate is the result of inductive signaals from the underlying endoderm, which include :Bone morphogenetic proteins (BMPs)
Basic fibroblast growth factors
Wnt proteins
After aligning into a cardiogenic crescent (~Day 20 in the human embryo), the precardiac cells differentiate and assemble as the bilateral heart tubes (24, 67). At this time, vasculogenesis is also taking place (65) as the formation of the vasculature is tightly correlated with heart development
Looping heart
As development proceeds, the primitive heart tube undergoes a series of complex events, which include chamber specification, septation, and trabeculation, to form the definitive four-chambered heart (Fig. 1). Defects in compartmentalization and proper communication between the four chambers account for the majority of human congenital heart defect (CHD; discussed below). Although the molecular mechanisms underlying cardiac morphogenesis remain largely unknaown, the production of mice in which specific genes were inactivated (“knockouts”) has allowed the identification of proteins involved in chamber maturation and heart morphogenesis (Table 1). Chamber specification is a very early event since the beating heart tube is organized with an anteroposterior polarity anad specific segments are already fated to become, from anterior to posterior, the aortic sac, the conotruncus, the right ventricle, the left ventricle, the atria, and the sinus venosus of the mature heart (Fig. 1). Thus, subtle alterations in early myocyte differentiation could lead to defects in cardiac looping, septation, and compartmentalization. The mechanisms controlling heart tube regionalization are not fully understood.
Chamber formation
In addition to heart-tube-derived myocytes, the mature
heart contains myocytes derived from a distinct heart field,
located in the pharyngeal mesoderm and referred to as the
secondary or anterior heart field (AHF) [30]. Cells from the
AHF are incorporated in the growing heart tube during
the looping stage at the venous and arterial poles. Recently, it
was shown that the myocardium of the right ventricle is
derived from the AHF, further underlining the differences
between the two ventricular compartments [31,32]. The fact
that myocardial cells appear to derive from two embryological
distinct mesodermal lineages is important in understanding
the molecular basis of diseases that differentially
affect the left or right ventricles.
The subsequent stages involve a series of complex steps during which the tubular heart is transformed into a multichambered organ
Factors:
GATA-4
NKX 2.5
TBX 5
HAND 1
HAND 2
GATA-4
nevertheless, transcription
factor (TF) GATA-4, initially identified as one of the key TFs
required for expression of the cardiac natriuretic peptide
genes NPPA and NPPB, is emerging as the critical regulator
of the earliest stages of cardiogenesis. First, GATA-4 is the
competence factor required to allow cells to respond to
cardioinductive substances [1,2], and its combined action
with another TF, Nkx2.5, mediates BMP signaling [3].
During in vitro cardiogenesis, GATA-4 expression precedes
that of Nkx2.5 and several other cardiac regulators and is
essential for survival of cardioblasts [4]. GATA-4 acts
synergistically with the SMAD proteins, the intracellular
effectors of the TGF/BMP signaling pathway to activate
Nkx2.5 transcription [5]. Ectopic GATA-4 expression is
sufficient to induce cardiogenesis in ES cells and in Xenopus
embryonic ectoderm [6]. GATA-4 cardiogenic activity
reflects its activation of cardiogenic growth factors like
BMP-4 [7] as well as other TFs required for heart formation
[8,9]. Thus, GATA-4 is a central player of a self-reinforcing
feedback loop at the onset of cardiogenesis.
NKX 2.5
Although Nkx2.5 is expressed
uniformly throughout the heart, detailed analyses of a
null mutation of Nkx2.5 in mice suggest that Nkx2.5 is
required for proper chamber specification. In human,
mutations in Nkx2.5 are associated with septal and
conduction defects
TBX 5
Another TF, Tbx5, a member of the growing family of
T-box factors, is essential for atrial formation, as evidenced
by the phenotype of null Tbx5 mice [14]. Tbx5 is the gene
mutated in Holt–Oram syndrome (HOS), an autosomal
dominant disease affecting heart and limb development.
Interestingly, mice with heterozygous deletion of Tbx5
recapitulate the full spectrum of HOS
HAND 1 & HAND 2
In addition, two
basic helix–loop–helix TFs, Hand1 and Hand2, which are
expressed in the precardiac mesoderm as well as in
noncardiac precursor cells, have been associated with right and left ventricular specification. Hand2 is expressed
throughout the straight heart tube but becomes restricted to
the future right ventricle during looping, while Hand1 is
restricted to the anterior and posterior regions of the heart
tube, which are fated to become the conotruncus and left
ventricle, respectively. Inactivation of the Hand2 gene in
mice results in embryonic lethality at the looping stage and
the segment of the heart tube destined to form the right
ventricle is absent [15]. Loss of Hand1 results in even earlier
embryonic lethality due to placentation defects, but chimeric
analysis (that rescues the placentation defect) suggests that
Hand1 is required to ensure proper cardiac looping
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