Deregulation of the Epithelial-to-Mesenchymal Transition Process Underlies Zic2-Linked Holoprosencephaly

Mutations in the Zic2 gene cause holoprosencephaly type 5, but the mechanisms that translate Zic2 mutations into this devastating pathology remain unclear. Here, we report that Zic2 is expressed in a few epiblast cells during gastrulation to become transiently upregulated in the primitive streak. Later, during neurulation, Zic2 is expressed in neural crest cells and downregulated as they delaminate from the neural tube. In combination with transcriptomic data from mutant embryos, chromatin occupancy profiles in gastrula and neural crest cells reveal that Zic2 regulates a large number of genes associated with the Wnt, cadherin and TGF-β pathways. Functional experiments in chick and mice demonstrate that Zic2 blocks the activation of the Wnt canonical pathway at the time that induces the TGF-β pathway to trigger cell delamination. All these experiments together demonstrate that Zic2 initiates epithelial-to-mesenchymal transition at early developmental stages.