Removal of Shh-expressing ectoderm (but not adjacent, Shh-negative ectoderm) resulted in craniofacial anomalies analogous to human cleft palate [53], indicating that the production of Shh within the ectoderm must play a critical signalling function, likely operating concurrently with the production of Shh from the endoderm, putatively to establish either paracrine feedback loops or to establish the appropriate concentration gradients to subsequently regulate downstream genetic targets. This evidence concerns the gene SHH and cleft palate.