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Heart Muscle Differentiation
Heart Muscle DifferentiationTHE HEART• Structure and function• Anatomy of the heart
HEART DEVELOPMENT• Overview of Heart Formation• Genetic factors regulating cardiac muscle differentiation
WHAT HAPPENS WHEN IT ALL GOES WRONG?• Congenital Heart Disease
WHAT ARE THE REQUIREMENTSOF A PUMP???
1. Receiving ChambersLeft and Right
Atria
2. Delivery Chambers
Left and Right Ventricles
3. Valves to direct the flow of blood
pulmonaryValve
WHAT ARE THE REQUIREMENTSOF A PUMP???
tricuspidValve
Aortic Valve
Mitral/Bicuspid Valve
IntercalatedDisc
Nucleus
4. Strongly contractile wall to provide the force required to propel blood
WHAT ARE THE REQUIREMENTS OF A PUMP?
CARDIAC MUSCLECELLS
•Cardiomyocytes
• contractile element of cardiac muscle
• elongated cells
• centrally located nucleus
• branched cells
• separated from each other by the presence of intercalated discs
• filled with rod-like bundles of myofibrils (contractile proteins s.a. myosin and Actin)
NucleusIntercalatedDisc
THE 6 REQUIREMENTS OF A PUMP
1. Receiving chambers
2. Delivery chambers
3. Valves to direct the flow of blood
4. Strong contractile wall to propel blood
5. Vessels to deliver blood
6. Conduction system to regulate the pump
MITRAL VALVE
TRICUSPID VALVE
PULMONARY VALVE
AORTIC VALVE
RIGHTATRIUM
INTERVENTRICULARSEPTUM
AORTA
PULMONARY ARTERY
LEFT ATRIUM
LEFT VENTRICLE
RIGHT VENTRICLE
ASCENDING AORTA
LEFT ATRIUM
LEFT ANTERIOR DESCENDINGCORONARY ARTERY
SUPERIOR VENA CAVA
INFERIOR VENA CAVA
RIGHT ATRIUM
CONDUCTION SYSTEM
AV NODE
SA NODE
5. Vessels to Deliver Blood6. Conduction System
HEART FORMATION
• Gastrulation - formation of 3 germ layers
• ENDODERM• ECTODERM• MESODERM
• Heart is derived from the mesoderm
• First indication of human heart development is around day 16-19
• How do we progress from a single layer of mesoderm to the complex 3 dimensional structure of the heart???
Morphogenesis
differentiation• Genes
• Process of HeartFormation
CardiacCresent
Cardiac Progenitor
cells)
Cardiogenic Mesoderm
Endothelial (endocardial) Tubes
HEART FORMATION1. Formation of endocardial
tubes derived from mesodermal cells
2. Formation of the Primitiveheart tube
Primative/linear Heart Tube
Day 18 Day 22
FusingHearttubes
HEART FORMATION3. Primitive heart tube develops into 5 distinct regions
Day 22
FusingHearttubes
BulbusCordis
Ventricle
Sinus VenosusAtrium
TruncusArteriosus
HEART FORMATION4. Primitive heart tube Twists
Looping brings the distinct regions of the heart into the basic pattern that prefigures the adult structure
Atrium
Bulbus Cordis
Ventricle
Sinus Venosus
Truncus Arteriosus
Day 23
HEART FORMATIONThe bulbus cordis and truncus arteriosus have divided into two
vessels forming the aorta and pulmonary trunk
PulmonaryTrunk
Ventricle
Superiorvena cava
Atrium
Aorta
InferiorVena cava
Week 7 - the interatrial and interventricular septa have formedpartitioning the atria and ventricles into L and R compartments
Cardiac crescent stage
(E7.75)
Intra-embryonic coelomHeart progenitors
Linear heart tube(E8.0)
MyocardiumEndocardium
Looping heart(E10.5) Inter-ventricular septum
Trabeculae
Endocardial cushions
Conotruncal cushions
LVRV
Remodelling heart(E12.5) Inter-ventricular septumRV LV
LARAEndocardial cushions
Trabeculae
Atrial septum
Mouse Heart Formation
Neural Plate
Ectoderm
Cardiac Mesoderm
Head Mesoderm
Early identification of Cardiac Progenitorsin Mouse Embryo Day 7/7.5
E7.75
CardiacCresent
Cardiac Progenitor
cells)
Whole mouse embryo Transverse section
Heart Development in the Mouse
J.M. Icardo, 1997
AT WHAT STAGE DOES THEHEART START PUMPING?
• Human primitive heart begins contracting at day 22
• Mouse heart starts to contract around day 8
• Why does the heart start to contract so early???
GENETIC CONTROL OF HEART MUSCLECELL DIFFERENTIATION
• Genetic dissection of heart (dorsal vessel) formation inDrosophila has led to the identification of a number ofgenes implicated in heart determination
tinman
Dhand
bagp
ipe
Dmef2
dpp
twist
What does tinman do?
• homeobox gene
• identified in 1989 by Kim and Nirenberg
• localised to the dorsal mesoderm
• later stages to heart precursors and mesoderm
• Does tinman play a role in heart formation?
• Disco - identify cardial cells of the dorsal vessel
• visceral mesoderm expression in wt embryos
• tinman k/o - no heart or visceral mesoderm formation
• tinman expression is crucial for heart formation in drosophila
Does tinman play a role inheart development?
TRANSCRIPTIONAL CASCADE FOR CARDIOGENESIS IN DROSOPHILA
TWIST
Ventralmesoderm
Dorsalmesoderm
Heart Precursors
tinmanDpp Wg
tinman
D-mef2
Contractile protein genes
Cells committedto a cardiogenic fate
Activation oftranscription
D-mef2
• twist is essential for mesoderm formation
• 6 different genes related to tinmanwere isolated from divergentspecies
Nkx2-3Nkx2-5 (1993 Kamuro and Izumo,
Harvey 1996)Nkx2-6Nkx2-7Nkx2-8Nkx2-9
• evolutionary conservation
• Does Nkx2-5 have a similar function to tinman?
E7.75
Localisation of Nkx2.5 positive cells in thedeveloping mouse embryo using Lac Z Expression
CardiacCresent
Cardiac Progenitor
cells)
• Nkx2-5 expressed in the mesoderm
• later stages it is only expressed in the heart
• panel E shows no expression of Nkx2-5 in the lungs
• k/o Nkx2.5 there is no effecton early heart formation
• looping/twisting morphogenesis isaffected
Peri
-car
dial
Mus
cle
VM
Expression of Cardiac NK2-class Homeobox genes
tinman
Nkx2-5
Drosophila
Mouse
Chick
Zebrafish
Frog Nkx2-5
GENETIC CONTROL OF HEART MUSCLECELL DIFFERENTIATION
• Nkx2 class hoemobox genes are expressed during gastrulation in the lateral plate mesoderm (mouse, frog, avian and fish embryos)
• critical determinants of cardiac development
• Studies in Drosophila have shown tinman expression to be essential for heart development
• Absence of Nkx2-5 in the mouse doesn’t prevent theformation of the heart tube but blocks loopingand septum formation
CONSERVATION OF GENETIC PATHWAYS IN HEART DEVELOPMENT
CONSERVATION OF THE GENETIC PATHWAYS IN HEART DEVELOPMENT
Congenital Heart Disease• Defects present from birth
• affect <1 % of all children
• Morphogenesis of the heart has many stages
• Ample opportunity for something to go wrong
• Not surprising that abnormalities occur, perhapsmore surprising that the occurrence of abnormality is so infrequent.
Pulsatingtube
Twisting/rotatingheart
Septa Formation 4 Chamber Organ
Congenital Heart Disease
• What kind of abnormalities occur????
• Incomplete septa formation (holes between chambers)• Incorrect connection between chambers and vessels• valves that don’t function properly
• Atrial septal defect• ventricular septal defect• Tetralogy of Fallot
Atrial Septal Defect
• incomplete closure between 2 upper chambers• Blood returning from lungs flows through the hole• More blood flows through R side of heart• pulmonary hypertension• in most cases surgery can rectify this problem
• incomplete closure between 2 ventricles• Initially blood flows from R to L• heart dilates, pressure increases resulting in
pulmonary hypertension due to increased workload• in most cases spontaneous closure occurs•If needed surgery can rectify this problem
Ventricular Septal Defect
1. Ventricular septal defect2. Pulmonary stenosis (narrowing of pulmonary artery)3. Hypertrophy (thickening of the RV wall)4. Overriding aortaDecreased blood flow to the lungs and mixing of blood
Tetralogy of Fallot
• Recent investigations have mapped a mutation causing atrial septal defects to the NKX2-5 gene(Schott et al 1998)
• Decreased capacity of this transcription factor tobind DNA
• implicates Nkx2-5 in atrial septation and conduction system development
Nkx2-5 and Human Cardiac defects
More recent reviews
Buckingham et al 2005 Building The Mammalian Heart From Two Sources Of Myocardial Cells Nature reviews –genetics 6:826-835
Srivastava 2006 Making or Breaking the Heart: From
Lineage Determination to Morphogenesis Cell 126:1037-1048
NKX2-5 in ventricular muscle – Srivastava Nature 2004
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