title: Male differentiation of germ cells induced by embryonic age-specific Sertoli cells in mice.
abstract: Retinoic acid (RA) is a meiosis-inducing factor. Primordial germ cells (PGCs) in the developing ovary are exposed to RA, resulting in entry into meiosis. In contrast, PGCs in the developing testis enter mitotic arrest to differentiate into prospermatogonia. Sertoli cells express CYP26B1, an RA-metabolizing enzyme, providing a simple explanation for why XY PGCs do not initiate meios/is. However, regulation of entry into mitotic arrest is likely more complex. To investigate the mechanisms that regulate male germ cell differentiation, we cultured XX and XY germ cells at 11.5 and 12.5 days postcoitus (dpc) with an RA receptor inhibitor. Expression of Stra8, a meiosis initiation gene, was suppressed in all groups. However, expression of Dnmt3l, a male-specific gene, during embryogenesis was elevated but only in 12.5-dpc XY germ cells. This suggests that inhibiting RA signaling is not sufficient for male germ cell differentiation but that the male gonadal environment also contributes to this pathway. To define the influence of Sertoli cells on male germ cell differentiation, Sertoli cells at 12.5, 15.5, and 18.5 dpc were aggregated with 11.5 dpc PGCs, respectively. After culture, PGCs aggregated with 12.5 dpc Sertoli cells increased Nanos2 and Dnmt3l expression. Furthermore, these PGCs established male-specific methylation imprints of the H19 differentially methylated domains. In contrast, PGCs aggregated with Sertoli cells at late embryonic ages did not commit to the male pathway. These findings suggest that male germ cell differentiation is induced both by inhibition of RA signaling and by molecule(s) production by embryonic age-specific Sertoli cells.
authors.affiliation: Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Hawaii, USA. kohta@agr.ehime-u.ac.jp
authors.forename: Kohei
authors.initials: K
authors.lastname: Ohta
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Yanling
authors.initials: Y
authors.lastname: Lin
authors.forename: Nathanael
authors.initials: N
authors.lastname: Hogg
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Richard R
authors.initials: RR
authors.lastname: Behringer
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yamazaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000378:metabolism; D005260:Female; D005718:Gametogenesis / Q000235:genetics*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000166:cytology*; D008297:Male; D008540:Meiosis / Q000502:physiology; D051379:Mice; D008938:Mitosis / Q000235:genetics; D011506:Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors; D012708:Sertoli Cells / Q000502:physiology*; D015398:Signal Transduction; D014212:Tretinoin / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C477341:Nanos2 protein, mouse; D011506:Proteins; D016601:RNA-Binding Proteins; D018168:Receptors, Retinoic Acid; C102019:Stra8 protein, mouse; D014212:Tretinoin; D015254:DNA Modification Methylases; C558169:Dnmt3a1 protein, mouse