Shh directs cell-cycle exit by activating p57Kip2 in the zebrafish retina.
The Hedgehog (Hh) family of signalling proteins control both differentiation and proliferation during animal development. Previous studies have shown that Hh signalling has a stimulatory effect on the cell cycle in several organs by controlling core cell-cycle components. Here, we show that Sonic hedgehog (Shh) signalling has the opposite effect in the zebrafish retina, where it leads to cell-cycle exit, and that this is mediated by transcriptional activation of the cyclin kinase inhibitor p57Kip2. The loss of p57Kip2 activity strongly resembles the Shh mutant eye phenotype, and overexpression of p57Kip2 rescues cell-cycle exit in Shh mutants, indicating that p57Kip2 is both necessary and sufficient to mediate Shh-induced cell-cycle exit in the retina. These findings raise the possibility that stimulation of cell-cycle exit through regulation of core cell-cycle components may be part of a general mechanism required for Hh-directed differentiation.
Shkumatava
Alena
A
EMBL Heidelberg, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Neumann
Carl J
CJ
D000818:Animals; D001973:Bromodeoxyuridine; D002453:Cell Cycle; D002454:Cell Differentiation / Q000502:physiology; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D053823:Hedgehog Proteins; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008845:Microinjections; D009687:Nuclear Proteins / Q000378:metabolism*; D016376:Oligonucleotides, Antisense; D012160:Retina / Q000196:embryology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology*
D050761:Cyclin-Dependent Kinase Inhibitor p57; D053823:Hedgehog Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D015534:Trans-Activators; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine