Int J Biol Sci 2019; 15(9):2006-2015. doi:10.7150/ijbs.31451
p53 Mutant p53N236S Induces Neural Tube Defects in Female Embryos Abnormal Cellular Proliferation, Differentiation and Apoptosis are Involved in the Gain of Function of p53N236S that Induces Female-specific Neural Tube Defects
Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, Chenggong Campus, 727 South Jingming Road, Kunming, Yunnan 650500, China
The p53 is one of the most important tumor suppressors through surveillance of DNA damages and abnormal proliferation signals, and activation the cell cycle arrest and apoptosis in response to stress. However, the mutation of p53 is known to be oncogenic by both loss of function in inhibiting cell cycle progress and gain of function in promoting abnormal proliferation. In the present study, we have established a knock in mouse model containing an Asn-to-Ser substitution at p53 amino acid 236 by homologous recombination (p53N236S). Other than tumorigenesis phenotype, we found that p53S/S mice displayed female-specific phenotype of open neural tube in brain (exencephaly) and spinal cord (spina bifida). The occurrence rate for embryonic exencephaly is 68.5% in female p53S/S mice, which is much more than that of in p53-/- mice (37.1%) in the same genetic background. Further study found that p53N236S mutation increased neuronal proliferation and decreased neuronal differentiation and apoptosis. To rescue the phenotype, we inhibited cell proliferation by crossing Wrn-/-mice with p53S/S mice. The occurrence of NTDs in p53S/S Wrn-/-mice was 38%, thus suggesting that the inhibition of cell proliferation through a Wrn defect partially rescued the exencephaly phenotype in p53S/S mice. We also report that p53S decreased expression of UTX at mRNA and protein level via increasing Xist transcript, result in high female-specific H3K27me3 expression and repressed Mash1 transcription, which facilitating abnormal proliferation, differentiation, and apoptosis, result in the mis-regulation of neurodevelopment and neural tube defects (NTDs).
Keywords: p53N236S, neural tube defects, H3K27me3
Zhao J, Tian Y, Zhang H, Qu L, Chen Y, Liu Q, luo Y, Wu X. p53 Mutant p53N236S Induces Neural Tube Defects in Female Embryos Abnormal Cellular Proliferation, Differentiation and Apoptosis are Involved in the Gain of Function of p53N236S that Induces Female-specific Neural Tube Defects. Int J Biol Sci 2019; 15(9):2006-2015. doi:10.7150/ijbs.31451. Available from http://www.ijbs.com/v15p2006.htm