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Embryos with homozygous mutation of <i>Eftud2</i> in their neural crest cells (<i>Eftud2^ncc−/−</i>) have brain and craniofacial malformations, hyperactivation of the P53-pathway and die before birth. Treatment of <i>Eftud2^ncc−/−</i> embryos with pifithrin-α, a P53-inhibitor, partly improved brain and craniofacial development. To uncover if craniofacial malformations and death were indeed due to P53 hyperactivation we generated embryos with homozygous loss of function mutations in both <i>Eftud2</i> and <i>Trp53</i> in the neural crest cells. We evaluated the molecular mechanism underlying craniofacial development in pifithrin-α-treated embryos and in <i>Eftud2</i>; <i>Trp53</i> double homozygous (<i>Eftud2^ncc−/−</i>; <i>Trp53^ncc−/−</i>) mutant embryos. <i>Eftud2^ncc−/−</i> embryos that were treated with pifithrin-α or homozygous mutant for <i>Trp53</i> in their neural crest cells showed reduced apoptosis in their neural tube and reduced P53-target activity. Furthermore, although the number of SOX10 positive cranial neural crest cells was increased in embryonic day (E) 9.0 <i>Eftud2^ncc−/−</i>; <i>Trp53^ncc−/−</i> embryos compared to <i>Eftud2^ncc−/−</i> mutants, brain and craniofacial development, and survival were not improved in double mutant embryos. Furthermore, mis-splicing of both P53-regulated transcripts, <i>Mdm2</i> and <i>Foxm1</i>, and a P53-independent transcript, <i>Synj2bp</i>, was increased in the head of <i>Eftud2^ncc−/−</i>; <i>Trp53^ncc−/−</i> embryos. While levels of <i>Zmat3</i>, a P53- regulated splicing factor, was similar to those of wild-type. Altogether, our data indicate that both P53-regulated and P53-independent pathways contribute to craniofacial malformations and death of <i>Eftud2^ncc−/−</i> embryos.