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 (Cambridge, England). 139(15):2711-2720.
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.