SHH and holoprosencephaly: Hh signaling requires interaction with GLI proteins in both activator (A) and repressor (R) form; therefore loss of GLIR in the talpid3 limb results in polydactyly, (due to loss of repression of Hh signaling targets by GLIR), while craniofacial abnormalities can be attributed to a loss of GLIA but are partially rescued by lack of GLIR also, producing variable holoprosencephaly that is less severe than SHH−/− mutants.27