title: Neuregulins are essential for spermatogonial proliferation and meiotic initiation in neonatal mouse testis.
abstract: The transition from mitosis to meiosis is unique to germ cells. In murine embryonic ovaries and juvenile testes, retinoic acid (RA) induces meiosis via the stimulated by retinoic acid gene 8 (Stra8), but its molecular pathway requires elucidation. We present genetic evidence in vivo and in vitro that neuregulins (NRGs) are essential for the proliferation of spermatogonia and the initiation of meiosis. Tamoxifen (TAM) was injected into 14-day post-partum (dpp) Sertoli cell-specific conditional Nrg1(Ser-/-) mutant mice. TAM induced testis degeneration, suppressed BrdU incorporation into spermatogonia and pre-leptotene primary spermatocytes, and decreased and increased the number of STRA8-positive and TUNEL-positive cells, respectively. In testicular organ cultures from 5-6 dpp wild-type mice and cultures of their re-aggregated spermatogonia and Sertoli cells, FSH, RA [all-trans-retinoic acid (ATRA), AM580, 9-cis-RA] and NRG1 promoted spermatogonial proliferation and meiotic initiation. However, TAM treatment of testicular organ cultures from the Nrg1(Ser-/-) mutants suppressed spermatogonial proliferation and meiotic initiation that was promoted by FSH or AM580. In re-aggregated cultures of purified spermatogonia, NRG1, NRG3, ATRA and 9-cis-RA promoted their proliferation and meiotic initiation, but neither AM580 nor FSH did. In addition, FSH, RAs and NRG1 promoted Nrg1 and Nrg3 mRNA expression in Sertoli cells. These results indicate that in juvenile testes RA and FSH induced meiosis indirectly through Sertoli cells when NRG1 and NRG3 were upregulated, as NRG1 amplified itself and NRG3. The amplified NRG1 and NRG3 directly induced meiosis in spermatogonia. In addition, ATRA and 9-cis-RA activated spermatogonia directly and promoted their proliferation and eventually meiotic initiation.
authors.affiliation: Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Kumamoto 860-8555, Japan.
authors.forename: JiDong
authors.initials: J
authors.lastname: Zhang
authors.forename: Ko
authors.initials: K
authors.lastname: Eto
authors.forename: Asuka
authors.initials: A
authors.lastname: Honmyou
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nakao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Abé
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D008297:Male; D008540:Meiosis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D020880:Neuregulins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018739:Oncogene Proteins v-erbB / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013093:Spermatogonia / Q000166:cytology / Q000502:physiology*; D013723:Teratogens / Q000494:pharmacology; D013737:Testis / Q000166:cytology* / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D046509:Tissue Culture Techniques; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D001565:Benzoates; D020880:Neuregulins; D018739:Oncogene Proteins v-erbB; D012333:RNA, Messenger; D013723:Teratogens; D013764:Tetrahydronaphthalenes; C068073:Am 580; D014212:Tretinoin; D005640:Follicle Stimulating Hormone