Mis-splicing of Mdm2 leads to increased P53-activity and craniofacial defects in a MFDM Eftud2 mutant mouse model
2020
EFTUD2, 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 in Eftud2 and used Wnt1-Cre2 to delete it in neural
crest cells. Homozygous deletion of Eftud2 leads 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 of Mdm2 transcripts 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 of
EFTUD2 are a result of mis-splicing of Mdm2 and P53-associated cell death. Hence,
drugs that reduce P53 activity may help prevent craniofacial defects associated with
spliceosomopathies.
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