Download genetic code +epigenetic regulation growth differentiation patterning

genetic code +epigenetic regulation
growth
differentiation
patterning
morphogenesis
Interactions between cells constitute the most important mechanism
regulating embryonic development
Cell-to-cell communication is mediated by signal molecules.
Interactions between cells constitute the most important mechanism
regulating embryonic development
Cell-to-cell communication is mediated by signal molecules.
SIGNAL MOLECULES REGULATING DEVELOPMENT:
Hedgehog
Wnt (wingless)
Transforming growth factor (TGF )
– Bone morphogenetic protein (BMP)
- Activin
Fibroblast growth factor (FGF)
Notch-ligands
Ephrins
Signal molecules regulate a variety of cellular functions, including
proliferation, differentiation, adhesion, migration and apoptosis
The same signals regulate development in different tissues and organs.
The response of a cell to signals is
determined by its COMPETENCE,
which is determined by the cell´s history.
Inductive signalling triggers the cells and tissues to adopt
a new direction of development
Hans Spemann
(1869-1941)
Inductive signalling triggers the cells and tissues to adopt
a new direction of development
Hans Spemann
(1869-1941)
80 years later: A two-headed frog by manipulating
Wnt and BMP signalling
The inductive effect of the
organizer is based on
inhibition of signaling
, Dkk
TGF signal transduction
TGF superfamily
signal molecules:
BMP
(bone morphogenetic proteins)
GDF
(growth & differentiation factors)
Activin
TGF
Inhibitors:
Extracellular:
- noggin, chordin,
- follistatin
- gremlin
Intracellular:
- smad 6/7, smurf 1/2
Wnt (Wg) signal transduction
Dickkopf (Dkk) inhibits Wnt signalling. It is needed for head
development
Wnt and BMP
signaling inhibited
Wnt signaling allowed
A.
B.
Dkk + dominant-negative BMP receptor
Dkk antibody injection
No head develops in the Dkk knockout mouse
Wild type
Dkk knockout mouse
Hedgehog signal transduction
Sonic hedgehog (Shh) expression in a 3-day old
chick embryo
Sonic hedgehog is the most important signal in the notochord.
It patterns the neural tube
Sonic hedgehog is the most important signal in notochord
Shh protein diffuses from the
notochord
Shh mRNA is restricted to
the notochord
Shh regulates the identities of neuronal subtypes
Shh is expressed in many signaling centers
Neural tube
Limb
Tooth
But signaling centers generally express many other signals too,
and signaling centers themselves are induced by signals
Discovery of the zone of polarizing activity (ZPA) in the limb bud
The effect of ZPA transplant was mimicked by a bead soaked in Shh protein .
Sonic hedgehog (Shh) is the polarizing signal
Fibroblast growth factor induces the initiation of limb
development
Agarose beads
FGF
Fibroblast growth factor receptors are tyrosine kinases
Signaling network during limb initiation
1. FGFs initiate limb development and induce ZPA formation and Shh
Somites
mesoderm
Ectoderm
2. Shh regulates BMP signaling by inducing gremlin a BMP inhibitor
in the progress zone (PZ).
ZPA= zone of polarizing activity
Many organs form as appendages of epithelium
Communication between the epithelium and mesenchyme
regulates the development of all organs developing as
epithelial appendages
Lung development
Lung branching is regulated by
several integrated signal pathways.
FGF-10 is expressed
in Mmesenchyme and induces epithelial proliferation and migration
Hair development
Sonic hedgehog is expressed in hair and feather placodes
Mouse
Placodes also express several FGFs, BMPs
and Wnts: they act as signalling centers
Chick
Lateral inhibition : An interplay between activating and inhibiting
signals regulates patterning:
The modulation of signal pathways in transgenic mice affects the patterning of placodes
control
Wnt signaling activated
Patterning of feathers by reaction-diffusion
and lateral inhibition mechanisms
Wnt
Dkk
Petterns created by ”morphogen gradients” and the ”reaction-diffusion model” (Turing model)
Kondo and Miura ,. Science, 2010
Signalling in Tooth Development
Thesleff, 2003
The enamel knot is a signalling center
regulating the shape of the tooth crown
p21
msx2
Lef1
BMP 2,4,7
Shh
FGF 3,4,9,20
Wnt 3,5,10a,10b
Shh
Secondary enamel knots regulate cusp development
E17
Occlusal view of enamel
knots in E17 epithelium.
1st molar of
a mouse
Secondary enamel knots regulate cusp development
E17
An activator-inhibitor loop of signalling
molecules has been hypothesized to
determine the exact morphological patterns
(Salazar-Ciudad and Jernvall, PNAS
99:8116,2002).
Occlusal view of enamel
knots in E17 epithelium.
1st molar of
a mouse
BMP induces enamel knot formation
Deletion of ectodin function in mice results in serious patterning defects:
Extra teeth, fusions of molars, and highly derived cusp patterns
•
Ectodin (Sostdc1) inhibits Wnt and
BMP signaling.
•
Conclusion: Fine tuning of signaling
is important for patterning.
•
Hypothesis: Fine tuning of signaling
may have been an important
mechanisms of the creation of
morphological diversity during
evolution
Inhibition of TGFbeta signaling reduces the number of teeth and disturbs patterning
Follistatin is an antagonist of Activin and BMPs.
Its overexpression inhibits these signal pathways