Regulation of male germline transmission patterns by the Trp53-Cdkn1a pathway

A small number of offspring are born from the numerous sperm generated from spermatogonial stem cells (SSCs). However, little is known regarding the rules and molecular mechanisms that govern germline transmission patterns. Here we report that the Trp53 tumor suppressor gene limits germline genetic diversity via Cdkn1a . Trp53 -deficient SSCs outcompeted wild-type (WT) SSCs and produced significantly more progeny after co-transplantation into infertile mice. Lentivirus-mediated transgenerational lineage analysis showed that offspring bearing the same virus integration were repeatedly born in a non-random pattern from WT SSCs. However, SSCs lacking Trp53 or Cdkn1a sired transgenic offspring in random patterns with increased genetic diversity. Apoptosis of KIT + differentiating germ cells was reduced in Trp53 - or Cdkn1a -deficient mice. Reduced CDKN1A expression in Trp53 -deficient spermatogonia suggested that Cdkn1a limits genetic diversity by supporting apoptosis of syncytial spermatogonial clones. Therefore, the TRP53-CDKN1A pathway regulates tumorigenesis and the germline transmission pattern. • Trp53 -deficient SSCs outcompete wild-type SSCs after competitive transplantation • Wild-type SSCs show a non-random germline transmission pattern by lineage analysis • Trp53- or Cdkn1a -deficient SSCs show random germline transmission patterns • Trp53 or Cdkn1a deficiency increases genetic diversity by apoptosis suppression SSCs exhibit an enormous genetic diversity. However, little is known regarding the rules and molecular mechanisms that govern germline transmission patterns. Kanatsu-Shinohara et al. show that TRP53 regulates the male germline transmission pattern by suppressing spermatogonial apoptosis via CDKN1A. Therefore, the TRP53-CDKN1A pathway regulates tumorigenesis and the germline transmission pattern.