Craniofacial Defects Persist in Eftud2 mutant mice with P53 Deletion
EFTUD2 is mutated in patients with mandibulofacial dysostosis with microcephaly (MFDM). We previously showed that homozygous deletion of Eftud2 in neural crest cells causes brain and craniofacial malformations, affecting the same precursors as in MFDM patients. This phenotype was partially rescued b...
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| Published in: | The FASEB journal Vol. 36; no. S1 |
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| Main Authors: | , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
The Federation of American Societies for Experimental Biology
01-05-2022
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| Online Access: | Get full text |
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| Summary: | EFTUD2 is mutated in patients with mandibulofacial dysostosis with microcephaly (MFDM). We previously showed that homozygous deletion of Eftud2 in neural crest cells causes brain and craniofacial malformations, affecting the same precursors as in MFDM patients. This phenotype was partially rescued by inhibition of the P53‐pathway using pifithrin‐α. Herein, we specifically evaluated the role of P53 in craniofacial abnormalities in Eftud2 mutants by genetically removing both Eftud2 and Trp53 in the neural crest cells (Eftud2‐P53 double knock‐outs (DKOs). We found that removing one or two alleles of Trp53 did not improve survival or craniofacial development in Eftud2 mutants. However, cleaved caspase‐3 immunostaining revealed that the abnormal increase in cell death found in Eftud2 mutants at E10.5 was reduced in the neural tube of Eftud2‐P53 neural crest DKOs. This suggests that the craniofacial abnormalities found in Eftud2‐P53 neural crest DKOs mutants are not only caused by apoptosis. We next aim to evaluate if cell cycle arrest could contribute to the phenotype. FoxM1 is a transcription factor which is essential for G2 progression into mitosis and is regulated by P53. We found increased splicing of FoxM1 in RNAseq experiments from Eftud2 mutants. Interestingly, the expression of the FoxM1 target, Cdc25b, was decreased by removal of P53 in Eftud2mutants as was that of Cdkn1a, a P53‐target required for mitosis. Altogether, our data suggest that in the presence of P53, Eftud2 mutants neural crest cells undergo apoptosis, whereas in the absence of this protein, they undergo cell cycle arrest. Ultimately, mis‐splicing leads to malformation in both a P53‐dependent and independent manner, which both ultimately contribute to a loss of neural crest cells and their derivative structures. |
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| ISSN: | 0892-6638 1530-6860 |
| DOI: | 10.1096/fasebj.2022.36.S1.R6027 |