SHH and holoprosencephaly: Shh, produced by the axial mesendoderm, prechordal mesoderm (PME), and notochordal plate, acts as a crucial signal in mammalian brain and facial development, and Shh gene alterations are the most frequent causes of autosomal-dominant inherited HPE in humans and Shh2/2 mouse embryos exhibit severe HPE [74–76].