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Effects of ETV5 (Ets Variant Gene 5) on Testis and Body Growth, Time Course of Spermatogonial Stem Cell Loss, and Fertility in Mice¹

Department of Veterinary Biosciences,³ University of Illinois at Urbana-Champaign, Urbana, Illinois 61802 Department of Pathology and Immunology,⁴ Howard Hughes Medical Institute,⁵ Washington University School of Medicine, St. Louis, Missouri 63110

ABSTRACT

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 µm² 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.

germ cells, sertoli cells, spermatogenesis, stem cell niche

¹This work was supported by the Billie A. Field Endowment, University of Illinois (to P.S.C.). The work at the University of Illinois was conducted in a facility constructed with support from Research Facilities Improvement Program Grant C06 RR16515 from the National Center for Research Resources, National Institutes of Health.

Correspondence: ²FAX: 217 244 1652; e-mail: p-cooke{at}uiuc.edu