S15-03 Activation of Wnt/β-catenin signalling in Xenopus embryos and cancer cells by de novo lipogenesis is associated with impaired formation of the primary cilium

The specification of cell types in the ventral half of the mouse neural tube depends on graded activity of the Sonic hedgehog (Shh) signaling pathway. Our genetic studies on neural patterning led to the surprising discovery that primary cilia are required for mammalian cells to transmit signals from the membrane protein Smoothened (Smo) to the Gli transcription factors. To understand why the primary cilium is an appropriate venue for Shh signal transduction, we are investigating the relationships among cilia genes and between cilia genes and the components of the Shh pathway that act between Smo and Gli proteins. Protein kinase A (PKA) is a conserved negative regulator that acts at that step of the pathway. We find that embryos that lack all PKA catalytic activity show a very strong activation of the pathway, and our data indicate that PKA activity depends on the presence of cilia. Costal2 is a negative regulator of the Shh pathway, and we find that the mouse homologue of Costal2, Kif7, has complex roles as both a negative and positive regulator of Shh signaling. Kif7 activity also depends on cilia, and the Kif7 protein appears to act as a motor within cilia. Finally, certain combinations of mutations in proteins that affect transport within the cilium partially restore normal Hedgehog signaling, suggesting that the balance of anterograde and retrograde trafficking within the cilium can control the level of signal output.