Abstract
Contrary to the canonical model of Hh signaling, we find that cells genetically lacking Ptch1 and Ptch2 remain responsive to ShhN. These cells retain the ability to migrate towards a source of ShhN, while expression of ShhN results in a robust activation of the transcriptional Hh response; both occur in a Smo-dependent manner. This activation of Hh responses does not require binding to the co-receptors Boc, Cdo, or Gas1, nor Shh autocatalytic processing, as the cholesterol moiety on Shh impedes signaling. Shh mutants unable to bind their cognate receptors, or fail to undergo proper processing, nevertheless retain their ability to activate the Hh response both in vivo and in vitro. Together, our findings support a model in which the role of Ptch1/2 as an inhibitor of Smo intersects with a Shh-mediated Smo activation event that is independent of known Shh receptors.