SHH and holoprosencephaly: Loss of a single copy of Shh, or mutations that lead to reduced expression of Shh in the PM, result in holoprosencephaly.22 The temporal perturbation of Shh signalling correlates with the severity of holoprosencephalic phenotypes: the earlier the alteration, the more severe the phenotype.23, 24 The tight temporal control of Shh in the PM is regulated by Nodal, which acts in a juxtacrine manner to control the duration of Shh expression.25 Elegant analyses in mouse show that Shh expression in RDVM cells is regulated by a unique enhancer, SBE2 (Shh brain enhancer 2).26