SMG5, a component of nonsense-mediated mRNA decay, is essential for the mouse spermatogonial differentiation and maintenance.

Mammalian spermatogenesis is a tightly controlled cellular process including spermatogonial development and differentiation, meiosis of spermatocyte, and the morphological specification of haploid spermatozoa, during which the post-transcriptional gene regulations are vital but poorly understood. Nonsense-mediated mRNA decay (NMD), a highly conserved post-transcriptional regulatory mechanism of gene expression in eukaryotes, recently emerges as a licensing mechanism in cell fate transition, including stem cell differentiation and organogenesis. The function of NMD in spermatogonial development remains elusive. Here we found knockout of SMG5, an important component of the NMD machinery, in embryonic germ cells led to the failure of spermatogenesis and male infertility. SMG5 null resulted in defective differentiation and maintenance of spermatogonia, which affected initiation of meiosis, ultimately caused a "Sertoli cell-only" phenotype. Transcriptome analysis revealed that SMG5 loss led to serious defects in NMD with targets features including PTC, long 3' UTR, and 5' uORFs. Furthermore, SMG5 loss downregulates gene transcripts involved in spermatogonia expansion and differentiation. During the spermatogonial differentiation, the deletion of SMG5 led to hyperactivation of the p38 MAPK signaling pathway, which triggered widespread cell death. These results suggest that SMG5 mediated NMD plays an important role in spermatogenesis by regulating the p38 MAPK signaling pathway.