L17 - Development of the Heart Flashcards
Leading cause of death worldwide
CVD
How many poeple in the UK died from CVD in the UK last year
152000
What is a congenital heart defect
A strucutral malformation of the heart which has arisen due to inappropriate development
Describe the heart structure of higher order vertebrates
4 chambers
2 atria 2 ventricles - to allow oxygenated and deoxygenated blood to be kept separate in the heart
2 different circulatory systems
Describe the heart structure of Xenopus
3 chambers
2 atria with the single ventricle - ox and deoxy blood are still kept separate
Describe the heat strucutre of zebrafish
2 chambered heart
Single atria and ventricle
Describe the heart of drosophila
Tubular heart
Single tube lined with valves to promote the unidirectional flow of blood - this is the simplest
Key processs in the morphological development of the heart
Cardiac mesoderm forms the cardiac cresent
Cells within the crescent migrate toward the midline to form a single tube
Once formed - asymmetric process of heart looping takes place
Maturation
Discuss how cardiac precurrosors are foudn
As a bilateral (2) populations of cells around the midline
Describethe formation of the heart tube
Cells migrate to the midline and fuse forming the heart tube
Describe heart looping
Heart tube undergoes asymmetric bending morphogenesis termed heart looping
What is maturation of the heart
THe formation of structures which are required for prooper fucntion
E.g. septa, trabeculae, valves etc.
What are the two population of cardiac precurrsors known as
First heart field cells
Second heart field cells
What do theFHF give rise to
Left ventricle, left atria, right atria
What doe the SHF cells give rise to
Right ventricle, left atria, right atria and outflow tract
Describe where cardiac cells are specified in FISH and in MOUSE
MOUSE - primitive streak
FISH - embryonic margin
What signalling is required for specification of the cardiac mesoderm
Non canonical Wnt signalling
What is required for specification of FHF cells
BMP
What is required for specification of the SHF cells
B-catenin / FGF
Once specified describe the migration of the FHF and SHF cells
FHF form the primitive heart tube
SHF in the adjacent mesoderm
The two heart field progenitors express
Different sets of factors
Both FHF and SHF express
Nkx2.5
Describe what happens where there is no Nkx2.5 present
Lack of primary myocytes in the heart
Describe the different heart pattenring events which lead to functional regionalisation
Chamber vs. non chamber
Atrial vs. ventricular contractility
Inflow, atrioventricular canal, outflow
Fucntional regionalisation of the heart is a complex
Interplay between activating and inhibitory factors
Notch - Tbx20 required for
Chamber myocardium
Nppa and nppb are markers of
Chamber myocaridium
BMP - TBx2 required for
Atrioventriuclar canal (AVC)
Describe the effect of Tbx2 mutant mice
Abnormal valve morphology
Abronormal Nppa expression (marker of chamber)
What is tbx20 requires for
What are the effects of tbx20 KOs
Required for the formation of chambers
Loss of expression of the chamber gene
Massive upregulation of Tbx2 throughout the heart
Tbx2 is a
Valve marker
Describe the interaction between Tbx20 and Tbx2
Tbx20 represses Tbx2
Describe what processes are involved in heart looping morphogenesis
Changes in cell shape
Growth of the heart tube
Asymmetric cell movements at the poles of the hearts
Regional changes in ECM
Lateralised cell signalling in the embryo
During heart looping morphogenesis what happens to the cells on the inner cruvature
Stay cubioidal
During heart looping morphogenesis what happens to the cells on the outer cruvature
Grow more and elongates causing a change in the orientation
What is myl7
Cardiac marker
Describe the growth of the heart tube
Initially made up of FHF cells surrounded by SHF cells
SHF add in at either pole
what does a Lac7 reported show regarding the lineage of cells that expressed islet 1
End up in the hart itself
Where is islet1 usually expressed
In the mesoderm adjacent to the heart
Describe what is seen in an insitu analysis of myl7 for Islet 1 mutant mice
Heart is reduced in size and looping is incorrect
What two conditions can be causes by L/R symmetry abnormalities
Which of theses is usually asymptomatic, which one is associated with signifcatnt pathology
Situs inversus - usually asymptomatic
Situs abmbiguous/heterotaxia - usually associated with significant pathology
What is associated with heterotaxia
Congenital heart defects
Where is nodal expressed prior to the formation of the organs
Left lateral plate mesoderm
Loss of nodal leads to
Disrupted organ symmetry
What is the ZF homolgue of nodal
spaw
Describe the role of the node in the asymetric expression of Spaw (nodal)
Node is a transient cup shaped organ with cilia which beat in a clockwise direction
This creates a directional fluid flow
Results in elevated Ca on the left side of the embryo
Results in increased Spaw on the left hand side of the embryo
What happens once Nodal reaches the more anterior regions of the embryo
Asymm expression of genes which are localisaed to specific organs
Describe the process/role of asymmetry in the development of the heart
asymmetric gene expression in the organ anlage
nodal target genes expressed in the left half of the cardiac disc
Asymmetric movement of the cells to form the heart tube
Cardiac disc undergoes rotation and involution to form a tube
Describe the effects of randomisation of lateralised gene expression in fish
Disruption to KV form or function results in randomisation of Spaw and directional heart dipalcemrnt
Describe the effects of randomisation of lateralised gene expression in humans
Individuals with mutations in cilary genes which cause primary cilary dyskinesia and also exhibit heterotaxia
What occurs when there is an absence of lateralised gene expression in Fish
Leads to failure of the leftward displacement of the heart tube
During heart development the heart is
Functional
What are the two forces acting in heart development
Cardiac contractility - one source of mechanical force in the dev. heart
Cardiac function causes blood to flow through the heart as it is developing
What is blood flow improtant for
Spatiotemporal gene expression of forming valves
Occurs through flow response genes
Required for maturation
Give an example of a flow response gene
Klf2
Describe what happens when the heart relaxes
What is the effect of this
Some retrograde flow through narrowins
Sensed by cells in adjacent regions
Genes which are required for valve formation are turned on