PMID:22782722

Citation	Stückemann, T, Wegleiter, T, Stefan, E, Nägele, O, Tarbashevich, K, Böck, G, Raz, E and Aanstad, P (2012) Zebrafish Cxcr4a determines the proliferative response to Hedgehog signalling. Development 139:2711-20
Abstract	The Hedgehog (Hh) pathway plays dual roles in proliferation and patterning during embryonic development, but the mechanism(s) that distinguish the mitogenic and patterning activities of Hh signalling are not fully understood. An additional level of complexity is provided by the observation that Hh signalling can both promote and inhibit cell proliferation. One model to account for this apparent paradox is that Hh signalling primarily regulates cell cycle kinetics, such that activation of Hh signalling promotes fast cycling and an earlier cell cycle exit. Here we report that activation of Hh signalling promotes endodermal cell proliferation but inhibits proliferation in neighbouring non-endodermal cells, suggesting that the cell cycle kinetics model is insufficient to account for the opposing proliferative responses to Hh signalling. We show that expression of the chemokine receptor Cxcr4a is a critical parameter that determines the proliferative response to Hh signalling, and that loss of Cxcr4a function attenuates the transcription of cell cycle regulator targets of Hh signalling without affecting general transcriptional targets. We show that Cxcr4a inhibits PKA activity independently of Hh signalling, and propose that Cxcr4a enhances Hh-dependent proliferation by promoting the activity of Gli1. Our results indicate that Cxcr4a is required for Hh-dependent cell proliferation but not for Hh-dependent patterning, and suggest that the parallel activation of Cxcr4a is required to modulate the Hh pathway to distinguish between patterning and proliferation.
Links	PubMed Online version:10.1242/dev.074930
Keywords	Alleles; Animals; Body Patterning; Cell Proliferation; Crosses, Genetic; Cyclic AMP-Dependent Protein Kinases/metabolism; Endoderm/cytology; Endoderm/metabolism; Green Fluorescent Proteins/metabolism; Hedgehog Proteins/metabolism; Kinetics; Mice; Neural Crest/cytology; RNA, Messenger/metabolism; Receptors, CXCR4/metabolism; Receptors, CXCR4/physiology; Signal Transduction; Transcription, Genetic; Zebrafish; Zebrafish Proteins/metabolism; Zebrafish Proteins/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
DANRE:Q7ZU02		GO:0008283: cell proliferation	ECO:0000315:		P		Figure 3: Results show that Cxcr4a is essential for endodermal cell proliferation	complete CACAO 6486
DANRE:Q7ZU02	involved_in	GO:0008283: cell population proliferation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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