Fibroblast growth factor-hedgehog interdependence during retina regeneration.
The embryonic chick is able to regenerate the retina after it has been removed. We have previously shown that proliferating stem/progenitor cells present in the ciliary body/ciliary marginal zone (CB/CMZ) of the chick eye are responsible for regeneration, which can be induced by ectopic fibroblast growth factor-2 (FGF2) or Sonic hedgehog (Shh). Here, we reveal the mechanisms showing how FGF2 and Shh signaling are interdependent during retina regeneration. If the FGF pathway is inhibited, regeneration stimulated by Shh is inhibited. Likewise, if the Hedgehog pathway is inhibited, regeneration stimulated by FGF2 is inhibited. We examined early signaling events in the CB/CMZ and found that FGF2 or Shh induced a robust Erk phosphorylation during the early stages of retina regeneration. Shh also up-regulated the expression of several members of the FGF signaling pathway. We show that ectopic FGF2 or Shh overexpression increased the number of phosphohistone 3 (PH3)-positive cells in the CB/CMZ and inhibition of either pathway decreased the number of PH3-positive cells. Additionally, both FGF and Hh signaling are required for cell survival in the CB/CMZ, whereas Hh and not FGF signaling plays a role in maintaining the identity of the retinal progenitor population in this region. Combined, our results support a model where the FGF and Hedgehog pathways work together to stimulate retina regeneration.
Spence
Jason R
JR
Department of Zoology, Miami University, Oxford, Ohio 45056, USA.
Aycinena
Juan-Carlos
JC
Del Rio-Tsonis
Katia
K
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D002642:Chick Embryo; D002924:Ciliary Body / Q000166:cytology / Q000196:embryology / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D012038:Regeneration / Q000235:genetics / Q000502:physiology*; D012160:Retina / Q000196:embryology / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
D053823:Hedgehog Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048049:Extracellular Signal-Regulated MAP Kinases