Lecture #2 Flashcards
Identify the period of time after fertilisation when the development is embryonic.
Everything from 2 cells to 8 weeks -> includes morula & blastocyst
–> then is foetal
Which stage of development is more susceptible to congenital abnormalities?
Embryonic (less so in foetal stages of development)
What is the embryo susceptible to - that can result in congenital abnormalities?
Highly sensitive to insult from teratogens (physical, chemical, or biological)
How do levels of susceptibility of the embryo & foetus change - at different time periods?
e.g., in week 3-7 CNS is in a high susceptibility time period - so major structural abnormalities could be at risk of occurring during this time
What are some causes of congenital abnormalities?
So most often - reasons are unknown
What are some causes of genetic diseases????? (NOT SURE IF GRAPH REFERS TO THIS???)
What do the majority of genetic diseases shown associations with?
95% of genetic diseases are associated with introns
–> non-coding DNA
What proportion of the % of genetic diseases with a link to non-coding DNA is within regulatory DNA (promoters & enhancers)?
73%!!!
What links to the 73% of genetic diseases in regulatory DNA of introns?
That 64% of these diseases are diseases of embryonic/foetal development
What do all of these %s show?
Non-coding DNA has an overwhelming contribution to disease (genetic disease) - with the majority influencing regulatory DNA (in these introns) & associated with foetal developmental issues
What % of pregnancies & births show morphological abnormalities?
-Pregnancy = 2.44%
-Births = 1.81%
–> is lower in births as many of these morphological abnormalities in pregnancy are incompatible with life - i.e., pregnancy does not make full term
Give examples of where morphological abnormalities in birth can be shown (with %s).
Percentage of births = 1.81%
-Nervous system = 0.09%
-Heart = 0.58%
-GI = 0.16%
-Urogenital = 0.4%
-Limb = 0.27%
-Chromosomal = 0.28%
What are the 3 subregions of the mesoderm?
-Chorda-paraxial mesoderm = chorda-mesoderm & paraxial mesoderm
-Intermediate mesoderm
-Lateral plate mesoderm
–> named according to their position in the trilaminar disc
–> all have distinct derivative tissues
-Mesoderm has started to adapt to certain identities at this stage
What does the paraxial mesoderm form/give rise to?
-Forms clusters of cells called somites - which lie on both sides along craniocaudal axis of neural tube
-4 occipital somites -> 8 cervical somites -> 12 thoracic somites -> 5 lumbar somites -> 5 sacral somites -> 8 coccygeal somites
-Each somite splits into dermatomes, myotomes, & sclerotomes
-Somites appear in ordered sequence cranial to caudal
-Sclerotomes - forms bone & cartilage of vertebrae, ribs & annulus fibrosus of intervertebral discs
-Dermatome - forms dermis & cutis of the back
-Myotome -forms all skeletal muscles
What does the intermediate mesoderm form/give rise to?
= Genitourinary system - includes kidneys & gonads
-Lies between lateral plate mesoderm & paraxial mesoderm
What does the lateral mesoderm form/give rise to?
-Most lateral
-Splits into parietal (somatic) & visceral (splanchnic) layers
Describe heart development.
-Mesodermal cells differentiate into cardiac cells (= the gist of it
-5 genes are important to controlling cell differentiation into cardiac cells - i.e., cardiac morphogenesis
-Mesodermal precardiac cells (= multipotent) - migrate to cephalic pole of embryo = forms cardiogenic crescent/FHF (first heart field)
-Cephalic & lateral inflexion of embryo causes crescent to migrate anteriorly & its 2 parts fuse on midline = forms primitive linear heart tube
–> this tube = made of inner endothelial layer & external myocardial layer (separated by cardiac jelly)
-These mesodermal precardiac cells differentiate into myocardial, endothelial & smooth muscle cells by progressive lineage restriction
-Myocardial cells differentiate into chamber-specific myocytes (atrial & ventricular) & conduction cells
Summarise heart development.
-Heart morphogenesis turns a tube into 4-chambered structure
-Separation occurs in ventricles, atria & outflow tract (which also has neural crest contribution)
What TF genes are involved in cardiac defect when mutated in mice or through studying patients?
-ASD = atrial septal defect
-AV= atrioventricular
-AVSD= atrioventricular septal defect
-DORV= double outlet right ventricle
-PDA= patent ductus arteriosus
-PS= pulmonary stenosis
-PTA= persistent truncus arteriosus
-TGA= transposition of great arteries
-TOF= tetralogy of Fallot
-VSD= ventricular septal defect
–> each TF binds to regulatory DNA (promotors & enhancers)
Describe limb development.
-Lateral plate mesoderm expresses Hox genes
-Forelimb buds emerge at level of cervical–thoracic boundary
–> where these forelimb buds form Hox-4,-5 stimulate expression of Tbx5 = anteriorly
-Hindlimb buds emerge at level of lumbar–sacral boundary
–> where these hindlimb buds form Hox-8,-9,-10 are involved in hindlimb formation - these Hox genes repress Tbx5 = marks posterior limit of forelimb field in anterior border of where these genes are expressed & Tbx4 expressed in region of hindlimb formation
===»> Tbx5 expression in location of future forelimb & Tbx4 & Pitx1 expression in location of future hindlimb - induces expression of FGF10 by lateral plane mesoderm
((Hox gene expression along anterior axis marks potential site for limb bud expression (along with retinoic acid) - i.e., Hox genes regulate patterning in formation of limbs))
-FGF10 stimulates overlying ectoderm (AER - Apical Ectodermal Ridge) to produce FGF8
= +ve feedback loop formed
–> these signals are sufficient to initiate & maintain limb bud outgrowth
-Retinoic acid = shown to be essential fot initiating limb bud outgrowth
–> AER stimulates proliferation of mesenchymal cells of the lateral plate mesoderm = forms small bud of mesenchymal cells
-Limb develops along proximodistal, anteroposterior & dorsoventral axes to attain its form & function
-Patterning & growth along 3 axes - controlled by limb-signalling centres = AER, zone of polarizing activity (ZPR) & nonridge ectoderm
–> AER = stimulates limb outgrowth based upon the patterning set out to it by Tbx expression:
Tbx5 expression will cause AER limb outgrowth to follow that of forelimb
Tbx4 expression will cause AER limb outgrowth to follow that of hindlimb
= outgrowth & results in limb identity (patterning)
- Proximodistal axis
–> from tip of appendage (distal) to where it joins body (proximal)
–> developing limb described along this axis has 3 regions:
-stylopod (proximal region of limb - forelimb = humerus & hindlimb = femur)
-zeugopod (mid-section of limb - forelimb = radius, ulna & hindlimb = tibia, fibula)
-autopod (distal region of limb - forelimb = hands/metacarpals & hindlimb = foot/phalanges) - Anteroposterior axis
–> ZPA - a mesenchymal posterior region of limb - secretes Shh signalling molecule (Sonic hedgehog) - all digits (except digit 1 = thumb & big toe) form by Shh activity
–> AER also has role in patterning to form limb
–> so ZPA develops limb bud to form along this axis
–> because Shh drives posterior identity in limb bud
[3. Dorsoventral axis] - not mentioned in ppt!!!
-Somites - provide dorsal signal to mesenchyme = dorsalises ectoderm
-Ectoderm in turn signals Wnt7a back to mesenchyme to pattern limb
What is Holt-Oram syndrome?
-Dominant ingerited genetic disease
-Cause = mutated Tbx5 gene
–> results in no stimulation of lateral plate mesoderm to express FGF10 - so +ve feedback loop not established
= no forelimb outgrowth = no arms
