We have recently identified the p53-related ΔNp63α gene as a transcriptional target ofBmp signaling that encodes a transcriptional repressor blocking neural developmentin the zebrafish ectoderm. However, in contrast to Bmps, the neural-repressing effectof forced ΔNp63α expression is restricted to the presumptive forebrain, whileposterior regions of the brain are not affected. Here, we show that this is due toinstability of ΔNp63α protein on the dorsal side of the embryo. In a yeast-two-hybridscreen, we isolated two ΔNp63α-modifying enzymes, the SUMO-conjugating enzymeUbc9 and the ubiquitin ligase Nedd4. The proteins bind to distinct sites in the Cterminalregion of ΔNp63α, which are absent in the shorter and more stable ΔNp63αisoform. Similarly, mutant versions of ΔNp63α unable to bind Nedd4 or Ubc9 arestabilized. ΔNp63α is sumoylated and ubiquitinated both in HEK293 cells and inzebrafish embryos, and Nedd4 promotes ubiquitination and instability of ?Np63?protein, with lysine residue 637 serving as a potential alternative sumoylation andubiquitination site that is crucial forΔNp63α destabilization. In zebrafish, ubc9.1 andnedd4 show restricted expression on the dorsal side of the embryo, where ΔNp63αinstability can be overcome upon blockage of endogenous Nedd4 activity, or uponinjection of mutant versions of ΔNp63α that are unable to bind Nedd4 or Ubc9. Thisresults in a more widespread neural repression, affecting the entire Bmp-sensitiveneuroectoderm. In sum, our data indicate that ΔNp63α is ubiquitinated in a Nedd4-and sumoylated in a Ubc9-dependent fashion, and that these modifications canregulate ΔNp63α stability in the zebrafish ectoderm.