Author:

Abstract:

NIPP1, for nuclear inhibitor of protein phosphatase 1 (PP1), is a multifunctional scaffold protein that regulates cell signaling, pre-mRNA splicing and transcription by targeting PP1 to specific nuclear substrates. The global deletion of NIPP1 in mice is embryonic lethal at the onset of gastrulation, precluding its functional analysis in adult tissues. This prompted us to generate a tamoxifen-inducible NIPP1 knockout (iKO) mouse model. Unexpectedly, the deletion of NIPP1 was not efficient in the examined organs except for testis. The loss of NIPP1 caused an age-dependent progressive loss of testicular germ cells, culminating in a Sertoli cells-only phenotype. iKO testis showed a decreased proliferation of (un)differentiated spermatogonia and an increased level of apoptosis. Likewise, neonatal iKO testis exhibited an almost complete loss of gonocyte-derived (un)differentiated spermatogonia during the first wave of spermatogenesis. In addition, GFRA1+ progenitor cells isolated from induced iKO testis displayed a reduced proliferation potential. These data suggest that NIPP1 is required for the maintenance of undifferentiated spermatogonia. We also found that the observed phenotype was associated with the deregulation of genes that are implicated in the control of cell proliferation and survival. At the molecular level, the deletion of NIPP1 was associated with the loss of core components of the Polycomb Repressive Complex 2 (PRC2), which affects gene expression through trimethylation of histone H3 at Lys 27. The loss of PRC2 components could be explained by the hyperphosphorylation and degradation of EZH2, the catalytic subunit of the PRC2 complex, resulting in the destabilization of other PRC2 core components. The testis phenotype of the iKOs could be phenocopied by the chemical inhibition of EZH1/2 in organotypic testis cultures. Overall, our study uncovers a key function for PP1-NIPP1 in the regulation of EZH2 phosphorylation and stability, which is essential for the maintenance of germ cells.