The morphogen signaling network in forebrain development and holoprosencephaly

Forebrain development is directed by secreted signaling molecules known as morphogens, and morphogen signaling defects often lead to failed midline induction and holoprosencephaly (HPE), the most common malformation of the human forebrain. Genetic studies in multiple organisms implicate 4 well-known morphogens or morphogen families-Nodal, Sonic hedgehog, Fibroblast growth factors, and Bone morphogenetic proteins-as causes of HPE. Here I review the roles of these morphogens in HPE and forebrain midline development. In particular, this review focuses on recent evidence for cross-regulatory interactions between morphogens, which lead to a signaling network model of forebrain development that can explain the distinctive HPE phenotypes seen in humans and animal models.