Fig. 5. Model for combined effects of Shh signaling and PI3K on cell cycle progression through Nmyc1 regulation in CGNP cultures. Previous work indicates that Shh signaling induces expression of the proto-oncogene transcription factor Nmyc1. Nmyc1 is necessary and sufficient for maintaining CGNP proliferation. The present findings indicate that maintenance of Nmyc1 protein levels in vitro is regulated in a Shh-independent manner. Our data support a role for IGFR signaling in activation of the PI3K pathway, which inhibits GSK3-mediated phosphorylation of Nmyc1 T50 and its subsequent degradation. The kinase priming Nmyc1 for GSK3 phosphorylation, by acting at S54, remains to be identified. Other growth factors (e.g. SDF-1) or cell-cell interactions (e.g. via integrins) are candidates for PI3K regulation and inhibition of GSK3 activity in vivo. The combined effect of concerted Shh and PI3K activity is to promote G1 progression and precisely control the timing of cell cycle exit.