Molecular mechanisms underlying Zic2-associated holoprosencephaly

Trabajo presentado al 17th Meeting of the Spanish Society for Developmental Biology (SEBD), celebrado de forma virtual del 18 al 20 de noviembre de 2020.Mutations in the gene ZIC2 causes holoprosencephaly type 5 (HPE5) and other neurodevelopmental disorders. However, the molecular mechanisms by which the reduction of the transcription factor ZIC2 leads to these pathologies remain unclear. Here we demonstrate that Zic2 is transiently expressed in premigratory neural crest cells (NCCs) during neurulation. Transcriptomic analysis of Zic2 mutant embryos at this stage reveal that this TF regulates pathways involved in the epithelial-to-mesenchymal transition process (EMT) such as the Wnt or TGF-β pathways. Further functional experiments in mouse and chicken embryos demonstrate that Zic2 facilitates NCC delamination by blocking canonical Wnt signaling at the time that activates the TGF-β pathway. Gastrulation is also a process highly dependent on EMT and, during this early stage, Zic2 is transiently expressed in primitive streak cells and pluripotent cells of the three germ layers of the epiblast. Zic2 occupancy profile analysis in gastrula and neural crest cells point out a key role for Zic2 as a master regulator of important signaling cascades such as the Wnt and TGF-β pathways during gastrulation and neurulation. These results define the signaling cascades affected in Zic2-associated pathologies and may contribute to improving the diagnosis and genetic counseling of these conditions.Peer reviewe