WNT responsive SUMOylation of ZIC5 exerts multiple effects on transcription to promote murine neural crest cell development

Zinc finger of the cerebellum (Zic) proteins act as classical transcription factors to promote transcription of the Foxd3 gene during neural crest cell specification. Additionally, they can act as co-factors that bind TCF molecules to repress WNT/{beta}-catenin dependent transcription without contacting DNA. Here, we show ZIC activity at the neural plate border is influenced by WNT-dependent SUMOylation. In a high WNT environment, a lysine within the highly conserved ZF-NC domain of ZIC5 is SUMOylated, which decreases formation of the TCF/ZIC co-repressor complex and shifts the balance towards transcription factor function. The modification is critical in vivo, as a ZIC5 SUMO-incompetent mouse strain exhibits neural crest specification defects. This work reveals the function of the ZIC ZF-NC domain, provides in vivo validation of target protein SUMOylation, and demonstrates that WNT/{beta}-catenin signalling directs transcription at non-TCF DNA binding sites. Furthermore, it can explain how WNT signals convert a broad domain of Zic ectodermal expression into a restricted domain of neural crest cell specification.