| Autor: |
Marius Wöste, Nina Neuhaus, Sibylle Mitschka, Hubert Schorle, Daniela Fietz, Lucia A. Torres-Fernández, Jana Emich, Yasmine Port, Manon S. Oud, Waldemar Kolanus, Michael Hölzel, Frank Tüttelmann, Sara Di Persio, Sabine Kliesch, Simon Schneider, Corinna Friedrich |
| Rok vydání: |
2021 |
| Předmět: |
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| DOI: |
10.1101/2021.02.01.429172 |
| Popis: |
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 the complex molecular network orchestrating germ cell development. TRIM71 is a stem cell-specific factor 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 conditionalTrim71knockout mouse (cKO) using the early primordial germ cell (PGC) markerNanos3as 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 developing germ cells in the testes’ seminiferous tubules. Infertility originates during embryogenesis, as the SCO phenotype was already apparent in neonatal mice. Thein vitrodifferentiation of mouse embryonic stem cells (ESCs) into PGC-like cells (PGCLCs) revealed reduced numbers of PGCLCs inTrim71-deficient cells. Furthermore,in vitrogrowth competition assays with wild type and CRISPR/Cas9-generatedTRIM71mutant NCCIT cells, a human GCT-derived cell line which we used as a surrogate model for proliferating PGCs, showed that TRIM71 promotes NCCIT cell proliferation and survival. Our data collectively suggest that germ cell loss in cKO mice results from combined defects during the specification and maintenance of PGCs prior to their sex determination in the genital ridges. Last, via exome sequencing analysis, we identified severalTRIM71variants in a cohort of infertile men, including a loss-of-function variant in a patient with SCO phenotype. Our work reveals for the first time an association ofTRIM71variants with human male infertility, and uncovers further developmental roles for TRIM71 in the generation and maintenance of germ cells during mouse embryogenesis. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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