Loss of Etv5 decreases proliferation and RET levels in neonatal mouse testicular germ cells and causes an abnormal first wave of spermatogenesis.
Mice that are ets variant gene 5 (ETV5) null (Etv5(-/-)) undergo the first wave of spermatogenesis but lose all spermatogonial stem cells (SSCs) during this time. The SSC loss in Etv5(-/-) mice begins during the neonatal period, suggesting a role for ETV5 in SSC self-renewal during this period. Herein, we show that Etv5 mRNA was present in perinatal mouse testis and that ETV5 was expressed in fetal Sertoli cells and by germ cells and Sertoli cells during the neonatal period. Transplantation of Etv5(-/-) germ cells failed to establish spermatogenesis in W/W(v) mice testes, indicating that germ cell ETV5 has a key role in establishment or self-renewal of transplanted SSCs. The SSC self-renewal is stimulated by glial cell-derived neurotrophic factor (GDNF) acting through the RET/GDNF family receptor alpha 1 (GFRA1) receptor complex in SSCs. Immunohistochemistry, quantitative PCR, and laser capture microdissection revealed decreased RET mRNA and protein expression in spermatogonia of neonatal Etv5(-/-) mice by Postnatal Days 4-8, indicating that disrupted GDNF/RET/GFRA1 signaling may occur before initial spermatogonial stem/progenitor cell decrease. Etv5(-/-) spermatogonia had reduced proliferation in vivo and in vitro. Decreased cell proliferation may cause the observed decreases in the number of type A spermatogonia (Postnatal Day 17) and daily sperm production (Postnatal Day 30) in Etv5(-/-) mice, indicating quantitative impairments in the first wave of spermatogenesis. In conclusion, ETV5 is expressed beginning in fetal Sertoli cells and can potentially have effects on neonatal Sertoli cells and germ cells. In addition, ETV5 has critical effects on neonatal spermatogonial proliferation, which may involve impaired signaling through the RET receptor.
Department of Veterinary Biosciences and Pathobiology, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
Gaurav
G
Tyagi
Kay
K
Carnes
Carla
C
Morrow
Natalia V
NV
Kostereva
Gail C
GC
Ekman
Daryl D
DD
Meling
Chris
C
Hostetler
Michael
M
Griswold
Kenneth M
KM
Murphy
Rex A
RA
Hess
Marie-Claude
MC
Hofmann
Paul S
PS
Cooke
D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D042282:Microdissection; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism; D012708:Sertoli Cells / Q000166:cytology / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics; D013093:Spermatogonia / Q000166:cytology / Q000378:metabolism; D013737:Testis / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C513242:Etv5 protein, mouse; C494989:Gfra1 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016222:Fibroblast Growth Factor 2; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse