Cardiogenesis Flashcards
Approx how many deaths in the UK are due to cardiovascular disease?
1 in 4
How often does someone have a heart attack in the UK?
Every 3 minutes
What is congenital heart disease?
The rise of defects during development which can manifest much later in life
They cause about 800 deaths per year where a thirs are in babies under 1 year old
What is health care cost around cardiovascular disease in the UK?
£11 billion per year
How many genes does a drosophila have?
13,000
How many of the 929 human disease genes do flies have homologous genes?
548
What do cardiac cells arise from?
Ventral lateral mesoderm called the splanchnopleura
What are the two different heart fields?
1) The first lays down the scaffold of the heart but cells have a low proliferative capacity
2) The second heart field lies next to the first and develops temporarily behind the fist. Has a higher proliferative capacity so contributes to growth of the heart
When do angiogenic clusters form?
Immediately after gastrulation
Where are angiogenic clusters formed from?
The ventral aspect of the lateral mesoderm
What does Dpp stand for?
decapentaplegic
Why does the corresponding between the dropsophila and vertebrate heart development eventually stop?
Because the drosophila heart does not show any looping or has any chambers
What is tinman?
Essential for heart formation in the drosophila
Transcription factor of homeobox
Where is tinman expressed?
Initially it is expressed throughout the embryo but is later restricted to the dorsal vessel
Later on it is restricted to the heart tube
What happens in a tinman mutant?
Failure to form the heart tube = no heart
What are the vertebrate homologues of tinman?
Belong to the Nk-2 family of homeobox transcription factors
eg Nk2.5
Where is Nk2.5 expressed?
In the cardiac crescent
Nk2.5 mice mutants show what?
Formation of a heart but it has cardiac defects at the looping stage
What induces Nk2.5 expression?
BMP signalling
How can you test if BMP induces Nk2.5?
Use a gain of function approach
eg soak a bead in BMP to induce ectopic expression
Where must a BMP soaked bead be placed in an embryo and why?
It must be placed in anterior mesoderm or anterior notochord
Posterior notochord secretes BMP inhibitors eg chordin which would block the effect of the bead
What is secreted in the anterior mesoderm to stop BMPs from being inhibited?
Wnt inhibitors eg serberus
These stop negative activity of Wnt pn BMP signalling
What are the steps involved in the formation of the heart tube?
1) 2 bilateral tubes form
2) Thickening of mesoderm round the tubes
3) Ventral migration occurs so cells come together in a ventral position
4) The tubes fuse and form a single endocardial tube surrounded by epimyocardium
What is epimyocardium?
Contains the precursor cells for the cardiac muscles
What is endocardium?
Contains the precursors of the endothelial lining of the heart and cushion cells that form valves
What does myocardium contain?
Myocytes of atria and ventricles
Purkinje fibres
What is induced by tinman?
Dmef2 (fly gene)
What is the vertebrate homologue of Dmef2?
Mef2A, B and C
Which of the Dmef2 homologues is expressed earliest in the heart?
Mef2c
Mef2c mutant shows what?
No heart looping and no right ventricule forms
Upregulation of Mef2B
Which genes are involved in the formation of the heart tube in vertebrates and drosophila?
V = GATA D = pannier
GATA 1-3 are involved in what process?
Hematopoesis
GATA 4-6 are involved in what process?
Cardiogenesis
GATA 4 is expressed earlies
What does a GATA 4 mouse mutant show?
Failure to form the heart tube
2 tubes remain in their lateral position
This is called cardiac bifida
Which direction does the heart loop?
To the right
What are the suggested mechanisms that explain why the heart loops to a particular direction?
a) Asymetric division
b) Asymetric cell death
c) changes in cell shape triggered by asymetric distribution of microtubules and actin bundles
What are lefty and nodal and where are they expressed?
TGFb related molecules
Expressed on the left of the embryo
When is the first asymetry established?
When signalling through activin receptor IIa inhibits Shh expression on the right side of the embryo
What does iv stand for?
Inversus viscerum
What does iv encode for?
A dynein - protein involved in the movement of cilia
What does inv stand for?
Inversion of embyonic turning - encodes for inversin, a protein containing ankyrin repeats found in cilia
Describe the proposed model that establishes and maintains asymetry
Inv and Iv are required for cilia movement and rotation
Cilia rotation establishes a preferential flow of Nodal and Lefty molecules to the left side of the embryo
What are dHand and Ehand?
bHLH transcription factors with specific expression in the left and right ventricles
What happens in dHand mutant mice?
They die at E10.5 and have right ventricle hypoplasia
What happens in eHand mutant mice?
Mice die at E8.5 with placental defects
What happens if mice have a conditional eHand mutation?
The mice survive until birth but they have a left vetricle defect
