Deregulation of the WNT and TGF-β signaling pathways underlies Zic2-associated holoprosencephaly

Resumen del póster presentado al European Developmental Biology Congress (EDBC), celebrado en Alicante del 23 al 26 de octubre de 2019.The transcription factor Zic2 is one of the genes most commonly mutated in patients with holoprosencephaly (HPE), and in mice Zic2 mutations recapitulate the HPE phenotype. It has been shown that Zic2 transcripts are expressed during early stages of development including gastrulation and neurulation, two processes that imply an epithelial to mesenchymal transition (EMT) step and involve both the Wnt and BMP/TGFβ pathways. Despite intense research trying to unveil Zic2 functions during these early stages of development, little is still known about the precise function or the molecular program controlled by this transcription factor. Here, we describe for the first time the spatiotemporal expression of Zic2 during mouse gastrulation and neurulation. This detailed characterization of Zic2 expression in the early embryo reveals that it is not specific of a particular germ layer (ectoderm, mesoderm and endoderm) but it is transiently and dynamically detected in those layers undergoing EMT. Later, Zic2 is expressed in premigratory Neural Crest (NC) cells and it is then downregulated as soon as these cells leave the neural tube. Then, by performing Zic2 ChIP-seq and RNA-seq assays in E6.0-6.5 and E8.0-8.5 embryos we unveiled the Zic2-binding regions across the genome and define the set of genes regulated by Zic2 during these stages that include many genes related to the Wnt and the BMP/TGFβ pathways. Functional experiments in mouse and chicken then demonstrate that Zic2 inhibits the Wnt canonical signalling pathway in NC cells and induces delamination.Peer reviewe