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Mutations affecting the germline can result in infertility or the generation of germ cell tumors (GCT), highlighting the need to identify and characterize the genes controlling germ cell development. The RNA-binding protein and E3 ubiquitin ligase TRIM71 is essential for embryogenesis, and its expression has been reported in GCT and adult mouse testes. To investigate the role of TRIM71 in mammalian germ cell embryonic development, we generated a germline-specific conditional  Trim71  knockout mouse (cKO) using the early primordial germ cell (PGC) marker  Nanos3  as a Cre-recombinase driver. cKO mice are infertile, with male mice displaying a Sertoli cell-only (SCO) phenotype which in humans is defined as a specific subtype of non-obstructive azoospermia characterized by the absence of germ cells in the seminiferous tubules. Infertility in male  Trim71  cKO mice originates during embryogenesis, as the SCO phenotype was already apparent in neonatal mice. The  in vitro  differentiation of mouse embryonic stem cells (ESCs) into PGC-like cells (PGCLCs) revealed reduced numbers of PGCLCs in  Trim71 -deficient cells. Furthermore, TCam-2 cells, a human GCT-derived seminoma cell line which was used as an  in vitro  model for PGCs, showed proliferation defects upon  TRIM71  knockdown. Additionally,  in vitro  growth competition assays, as well as proliferation assays with wild type and CRISPR/Cas9-generated  TRIM71  mutant NCCIT cells showed that TRIM71 also promotes proliferation in this malignant GCT-derived non-seminoma cell line. Importantly, the PGC-specific markers  BLIMP1  and  NANOS3  were consistently downregulated in  Trim71  KO PGCLCs,  TRIM71  knockdown TCam-2 cells and  TRIM71  mutant NCCIT cells. These data collectively support a role for TRIM71 in PGC development. Last, via exome sequencing analysis, we identified several  TRIM71  variants in a cohort of infertile men, including a loss-of-function variant in a patient with an SCO phenotype. Altogether, our work reveals for the first time an association of  TRIM71  deficiency with human male infertility, and uncovers further developmental roles for TRIM71 in the germline during mouse embryogenesis.

TRIM71 Deficiency Causes Germ Cell Loss During Mouse Embryogenesis and Is Associated With Human Male Infertility