Development - lecture slides * not learning outcomes Flashcards
Limbs
have distinct appearance but shared anatomical features
mechanisms of formation, patterning and development are very similar
the limb axes
anterior - posterior (head - tail)
proximal - distal (centre of body - away)
ventral - dorsal (front - back)
limb development
progressive
structures appear gradually
proportions change
highly regulated
highly homologous
initial outgrowth
induced from flank mesoderm
FGF signal
target genes include transcription factors - Tbx4, Tbx5, Brachyury (T)
in humans Tbx5 mutations are associated with Holt-Oram syndrome
the apical ectodermal ridge
AER is an ectoderm-derived structure
important signalling centre
function required through outgrowth
supplies FGF signals to maintain outgrowth
important in giving cells a proximal- distal identity
Progress zone model
proximal - distal patterning
is specified by the duration of time spent in the progress zome
time might be counted by cell divisions
FGF promotes cell divisions
two-signal model
proximal - distal patterning
opposing gradients of FGF-RA pattern the axis
high FGF = distal
high RA = proximal
known antagonism between FGF and RA
intermediate areas may adopt intermediate fates
FGF
fibroblast growth factor
RA
retinoic acid
the FGF signalling pathway
FGF binds the extracellular domain of the FGFR
triggers a conformational change in the receptor to activate its intracellular tyrosine kinase domain
resulting in a phosphorylation cascade of the tyrosine residues to activate downstream signalling pathways (MAPK)
> changes in gene expression to regulate cell growth, differentiation, survival and migration
the RA signalling pathway
RA binds to nuclear receptors
bind to RXR’s and heterodimerise
heterodimers bind to RARE DNA sequences in the promoter region
co-activators and co-repressors are recruited to regulate gene transcription
> cell differentiation, embryonic development, immune system regulation
tissue regeneration and repair
FGF-RA antagonism
FGF > promotes proliferation and inhibits Raldh2
RA > promotes differentiation, inhibits Fgf8 transcription and promotes Fgf8 transcript degradation
the polarising region
a region in the posterior
source of sonic hedgehog signals
acts as a morphogen to pattern the bud
grafting a ZPA results in mirror-image duplications
extent depends on size of graft/ strength of signal
sonic hedgehog
Shh is produced and secreted by signalling cells
Shh binds to PTCH1, relieving its inhibition of SMO
activated SMO triggers intracellular signalling
activation of Gli transcription factors which translocate to the nucleus and activates the expression of target genes involved in cell differentiation, patterning and growth
preaxial polydactyly
extra anterior digits
anterior Shh expression
long range gene regulatory region
