Effects of ETV5 (ets variant gene 5) on testis and body growth, time course of spermatogonial stem cell loss, and fertility in mice.

The transcription factor ets variant gene 5 (ETV5; also known as ERM) is essential for self-renewal of spermatogonial stem cells (SSCs). Mice with targeted disruption of Etv5 (Etv5(-/-)) undergo the first wave of spermatogenesis, but all SSCs are lost during this time, causing a Sertoli cell-only phenotype. This study examined body and testis growth and the time course of SSC loss in Etv5(-/-) mice to understand how loss of ETV5 impacts testicular and somatic development. Body weights were reduced in postnatal Etv5(-/-) males, indicating a role of ETV5 in growth. Testis weights and histology in Etv5(-/-) and wild-type (WT) males were similar at Postnatal Day 4, but testis weights were reduced at d8 and subsequently, indicating that ETV5 impacts postnatal testis growth. SSC density (SSCs per mum(2) of seminiferous tubule), estimated using an antibody against GFRA1, was similar in 4d WT and Etv5(-/-) mice. By 8 and 12d, GFRA1-positive cell density in Etv5(-/-) mice was decreased 17% and 32%, respectively, vs. WT. By 28d, GFRA1-positive cell density in Etv5(-/-) was reduced 95%, and GFRA1-positive cells were absent in 36d Etv5(-/-) males. In contrast to WT, 35- to 56-day-old Etv5(-/-) mice were infertile as assessed by natural breeding, artificial insemination, and in vitro fertilization, although motile sperm were present in epididymides of Etv5(-/-) mice during this time. In summary, initial testis development is normal in Etv5(-/-) mice despite decreased body weight, but SSC loss begins between 4 and 8d of age, indicating that ETV5 has effects beginning in the early neonatal period. Etv5(-/-) mice are infertile even when sperm is produced, indicating that ETV5 loss has other effects besides lack of SSC self-renewal that impair fertility.