Mis-splicing ofMdm2leads to Increased P53-Activity and Craniofacial Defects in a MFDMEftud2Mutant Mouse Model

Abstract

SummaryEFTUD2, a GTPase and core component of the splicesome, is mutated in patients with mandibulofacial dysostosis with microcephaly (MFDM). We generated a mutant mouse line with conditional mutation inEftud2and usedWnt1-Cre2to delete it in neural crest cells. Homozygous deletion ofEftud2leads to neural crest cell death and malformations in the brain and craniofacial region of embryos. RNAseq analysis of embryonic mutant heads revealed a significant increase in exon skipping, in retained introns and enriched levels ofMdm2transcripts lacking exon 3. Mutants also had increased nuclear P53, higher expression of P53-target genes, and increased cell death. Their craniofacial development was significantly improved when treated with Pifithrin-α, an inihibitor of P53. We propose that craniofacial defects caused by mutations ofEFTUD2are a result of mis-splicing ofMdm2and P53-associated cell death. Hence, drugs that reduce P53 activity may help prevent craniofacial defects associated with spliceosomopathies.