Activation of P53 pathway contributes to <i>Xenopus</i> hybrid inviability.

Abstract

Hybrid incompatibility as a kind of reproductive isolation contributes to speciation. The nucleocytoplasmic incompatibility between <i>Xenopus tropicalis</i> eggs and <i>Xenopus laevis</i> sperm (<i>t</i>_e×<i>l</i>_s) leads to specific loss of paternal chromosomes 3L and 4L. The hybrids die before gastrulation, of which the lethal causes remain largely unclear. Here, we show that the activation of the tumor suppressor protein P53 at late blastula stage contributes to this early lethality. We find that in stage 9 embryos, P53-binding motif is the most enriched one in the up-regulated Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) peaks between <i>t_e</i>×<i>l_s</i> and wild-type <i>X. tropicalis</i> controls, which correlates with an abrupt stabilization of P53 protein in <i>t</i>_e×<i>l</i>_s hybrids at stage 9. Inhibition of P53 activity via either <i>tp53</i> knockout or overexpression of a dominant-negative P53 mutant or Murine double minute 2 proto-oncogene (Mdm2), a negative regulator of P53, by mRNA injection can rescue the <i>t</i>_e×<i>l</i>_s early lethality. Our results suggest a causal function of P53 on hybrid lethality prior to gastrulation.