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Cellular nucleic acid binding protein (Cnbp) is a highly conserved single-stranded nucleic acid binding protein required for rostral head development. The use of a morpholino that inhibits Cnbp mRNA translation previously revealed a role of Cnbp in balancing neural crest cell apoptosis and proliferation in the developing zebrafish. Here, we report the use of another morpholino that specifically modifies the splicing of Cnbp pre-mRNA resulting in a reduction of full-length mRNA levels along with the generation of a novel transcript coding for an isoform that may act as dominant negative proteins. The use of this morpholino resulted in more severe phenotypes that enabled us to demonstrate that Cnbp loss-of-function adversely affects the formation and survival of craniofacial cartilaginous structures not only controlling the ratio of cell proliferation and apoptosis but also defining skeletogenic neural crest cell fate.