1. Cell cycle and differentiation
Exogenous control in multicellular organisms
Proliferation
Cell type-specific receptors
MAPK (ERK1/2)
b-catenin
Differentiation
MAPK/SMAD
Cell type-specific transcription factors

2. Cell Cycle G0 G1 S G2 M Terminal differentiation Replication Division
Rb, p53,
bHLH’s
CyB/CDK1 Id
CyD/CDK4
CyA/CDK2
CyE/CDK2

3. Proliferation Mitogens DNA synthesis Cell size integration
FGF, EGF, HGF
DNA synthesis
CyD/CDK4 accumulation
Degradation of Rb
Activation of E2F
Cell size integration
GSK3 inhibits CDK4
GSK3 inhibits b-Catenin

4. Differentiation bHLH transcription factors
Class A/general
TCF
Class B/Tissue specific
MyoD
Twist
Hairy
b-Catenin: bHLH-HDAC deactivator
Inhibitor of differentiation (Id)
HLH, no b
No b = no DNA binding

5. Myogenesis
GF-dependent commitment

6. Transcriptional cascades
??ACCREBPax
myf5/MyoDmyogenic program
MetHGF sensitivity
wnt
FGF[MAPK]CDK4cell proliferation
HGFcMetcell migration
WntFzdsh--|GSK3--|b-catenin
TCFproliferation
MyoDdifferentiation

7. Regeneration Satellite cells Repair recapitulates development
HGFcMet[MAPK]CyD
IGF1[PI3K]--|p27kip
Myostatin[SMAD]--|myoD
Ca2+CnNFAT/MEF2myogenin

8. Proliferation-differentiation competition
Rb/E2F
Rb/E2F dimers repress S-phase proteins
E2F activates S-phase proteins
Rb/Id
Rb/Id dimers bind MyoD & activate HDAC
Rb/Id activates differentiation
TCF/MyoD
TCF/b-catenin promotes cell cycle
MyoD/b-catenein promotes differentiation

9. Crosstalk between hypertrophy and hyperplasia
PI3K
mTOR increases protein synthesis
FOXO inhibition prevents apoptosis
GSK3 inhibition promotes cell cycle
Dsh
Fyn/RhoA promote adhesion & FAK
PLC/Cn promote specification