High-frequency developmental abnormalities in p53-deficient mice.
BACKGROUND
Several strains of mice carrying null mutations of the tumour suppressor gene p53 have been developed. It has been reported that homozygous mice from all of these strains develop normally to birth, but then succumb rapidly to neoplasia.


RESULTS
Here, we report that a significant proportion of female p53-/- mice die during embryogenesis or in the period between birth and weaning, being subject to a spectrum of abnormalities. In a significant proportion (23%) of p53-/- female embryos, the normal process of neural tube closure failed, leading to exencephaly and subsequent anencephaly. Although this phenomenon was predominantly associated with females, we observed one affected male embryo. In addition to a spectrum of neural tube defects, many of these embryos exhibited a range of craniofacial malformations, including ocular abnormalities and defects in upper incisor tooth formation. We observed a significant reduction in the number of p53-/- female progeny of p53+/- x p53+/- matings, and also in an in utero analysis of the p53+/- female progeny of p53-/- x p53+/+ matings. When male mice were exposed to irradiation prior to mating, a significant increase in the rate of abnormality was seen in the progeny, which was specifically associated with p53 deficiency.


CONCLUSIONS
We have identified a high rate of developmental abnormalities associated with p53 deficiency. This manifests itself as a spectrum of lesions, predominantly female-associated defects in neural tube closure. These defects may arise either because p53 plays a physiological role at the time of neural tube closure, or because of an abnormally high frequency of mutation within the haploid gametes of p53-null parents.
Armstrong
J F
JF
Department of Pathology, University Medical School, Edinburgh, UK.
Kaufman
M H
MH
Harrison
D J
DJ
Clarke
A R
AR
D000818:Animals; D000013:Congenital Abnormalities / Q000235:genetics*; D005314:Embryonic and Fetal Development / Q000235:genetics; D005260:Female; D005313:Fetal Death; D005720:Gamma Rays; D017353:Gene Deletion; D016158:Genes, p53; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011833:Radiation Injuries, Experimental