RRC ID 406
Author Masai I, Yamaguchi M, Tonou-Fujimori N, Komori A, Okamoto H.
Title The hedgehog-PKA pathway regulates two distinct steps of the differentiation of retinal ganglion cells: the cell-cycle exit of retinoblasts and their neuronal maturation.
Journal Development
Abstract In the developing zebrafish retina, neurogenesis is initiated in cells adjacent to the optic stalk and progresses to the entire neural retina. It has been reported that hedgehog (Hh) signalling mediates the progression of the differentiation of retinal ganglion cells (RGCs) in zebrafish. However, the progression of neurogenesis seems to be only mildly delayed by genetic or chemical blockade of the Hh signalling pathway. Here, we show that cAMP-dependent protein kinase (PKA) effectively inhibits the progression of retinal neurogenesis in zebrafish. Almost all retinal cells continue to proliferate when PKA is activated, suggesting that PKA inhibits the cell-cycle exit of retinoblasts. A cyclin-dependent kinase (cdk) inhibitor p27 inhibits the PKA-induced proliferation, suggesting that PKA functions upstream of cyclins and cdk inhibitors. Activation of the Wnt signalling pathway induces the hyperproliferation of retinal cells in zebrafish. The blockade of Wnt signalling inhibits the PKA-induced proliferation, but the activation of Wnt signalling promotes proliferation even in the absence of PKA activity. These observations suggest that PKA inhibits exit from the Wnt-mediated cell cycle rather than stimulates Wnt-mediated cell-cycle progression. PKA is an inhibitor of Hh signalling, and Hh signalling molecule morphants show severe defects in cell-cycle exit of retinoblasts. Together, these data suggest that Hh acts as a short-range signal to induce the cell-cycle exit of retinoblasts. The pulse inhibition of Hh signalling revealed that Hh signalling regulates at least two distinct steps of RGC differentiation: the cell-cycle exit of retinoblasts and RGC maturation. This dual requirement of Hh signalling in RGC differentiation implies that the regulation of a neurogenic wave is more complex in the zebrafish retina than in the Drosophila eye.
Volume 132(7)
Pages 1539-53
Published 2005-4
DOI 10.1242/dev.01714
PII dev.01714
PMID 15728672
MeSH Animals Cell Cycle / drug effects Cell Cycle / physiology Cell Differentiation / drug effects Cell Differentiation / physiology* Colforsin / pharmacology Cyclic AMP-Dependent Protein Kinases / metabolism* DNA-Binding Proteins / biosynthesis DNA-Binding Proteins / genetics Gene Expression / drug effects Growth Substances / biosynthesis Growth Substances / genetics Hedgehog Proteins Intercellular Signaling Peptides and Proteins / physiology Mitosis / physiology Neurons / cytology Neurons / enzymology Neurons / metabolism Oncogene Proteins / metabolism Receptors, G-Protein-Coupled / metabolism Retina / embryology* Retinal Ganglion Cells / cytology Retinal Ganglion Cells / enzymology* Retinal Ganglion Cells / metabolism Trans-Activators / metabolism* Transcription Factors / metabolism Wnt Proteins Zebrafish / embryology* Zebrafish Proteins / biosynthesis Zebrafish Proteins / genetics Zinc Finger Protein GLI1
IF 5.763
Times Cited 74
Zebrafish rw021(Tg(ath5:GFP) )?