Apical constriction is a basic mechanism for epithelial morphogenesis, making columnar cells into wedge shape and bending a flat cell sheet. It has long been thought that an apically localized myosin generates a contractile force and drives the cell deformation. However, when we tested the increased apical surface contractility in a cellular Potts model simulation, the constriction increased pressure inside the cell and pushed its lateral surface outward, making the cells adopt a drop shape instead of the expected wedge shape. To keep the lateral surface straight, we considered an alternative model in which the cell shape was determined by cell membrane elasticity and endocytosis, and the increased pressure is balanced among the cells. The cellular Potts model simulation succeeded in reproducing the apical constriction, and it also suggested that a too strong apical surface tension might prevent the tissue invagination.

Missense ‘hotspot’ mutations localized in six p53 codons account for 20% of TP53 mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether and how they may gain additional functions promoting tumorigenesis remain controversial. Here, we generated Trp53^Y217C, a mouse model of the human hotspot mutant TP53^Y220C. DNA damage responses were lost in Trp53^Y217C/Y217C (Trp53^YC/YC) cells, and Trp53^YC/YC fibroblasts exhibited increased chromosome instability compared to Trp53^-/- cells. Furthermore, Trp53^YC/YC male mice died earlier than Trp53^-/- males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes in Trp53^YC/YC thymic cells compared to Trp53^-/- cells. Surprisingly, we recovered only one Trp53^YC/YC female for 22 Trp53^YC/YC males at weaning, a skewed distribution explained by a high frequency of Trp53^YC/YC female embryos with exencephaly and the death of most Trp53^YC/YC female neonates. Strikingly, however, when we treated pregnant females with the anti-inflammatory drug supformin (LCC-12), we observed a fivefold increase in the proportion of viable Trp53^YC/YC weaned females in their progeny. Together, these data suggest that the p53^Y217C mutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.