title: Fetal Leydig Cells Persist as an Androgen-Independent Subpopulation in the Postnatal Testis.
abstract: Two distinct types of Leydig cells emerge during the development of eutherian mammals. Fetal Leydig cells (FLCs) appear shortly after gonadal sex differentiation, and play a crucial role in masculinization of male fetuses. Meanwhile, adult Leydig cells (ALCs) emerge after birth and induce the secondary male-specific sexual maturation by producing testosterone. Previous histological studies suggested that FLCs regress completely soon after birth. Furthermore, gene disruption studies indicated that androgen signaling is dispensable for FLC differentiation but indispensable for postnatal ALC differentiation. Here, we performed lineage tracing of FLCs using a FLC enhancer of the Ad4BP/SF-1 (Nr5a1) gene and found that FLCs persist in the adult testis. Given that postnatal FLCs expressed androgen receptor (AR) as well as LH receptor (LuR), the effects of AR disruption on FLCs and ALCs were analyzed by crossing AR knockout (KO) mice with FLC-specific enhanced green fluorescent protein (EGFP) mice. Moreover, to eliminate the influence of elevated LH levels in ARKO mice, LuRKO mice and AR/LuR double-KO mice were analyzed. The proportion of ALCs to postnatal FLCs was decreased in ARKO mice, and the effect was augmented in the double-KO mice, suggesting that androgen signaling plays important roles in ALCs, but not in FLCs. Finally, ARKO was achieved in an FLC-specific manner (FLCARKO mice), but the FLC number and gene expression pattern appeared unaffected. These findings support the conclusion that FLCs persist as an androgen-independent Leydig subpopulation in the postnatal testis.
authors.affiliation: Department of Molecular Biology (Y.S., S.M., K.M., H.O., T.B., K.-i.M.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Soma Central Hospital (S.K.), Soma, Fukushima 976-0016, Japan; Institute of Reproductive and Developmental Biology (I.H.), Department of Surgery and Cancer, Imperial College London, London W12 0NN, United Kingdom; and Department of Physiology (I.H.), University of Turku, 20520 Turku, Finland.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shima
authors.affiliation: Department of Molecular Biology (Y.S., S.M., K.M., H.O., T.B., K.-i.M.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Soma Central Hospital (S.K.), Soma, Fukushima 976-0016, Japan; Institute of Reproductive and Developmental Biology (I.H.), Department of Surgery and Cancer, Imperial College London, London W12 0NN, United Kingdom; and Department of Physiology (I.H.), University of Turku, 20520 Turku, Finland.
authors.forename: Sawako
authors.initials: S
authors.lastname: Matsuzaki
authors.affiliation: Department of Molecular Biology (Y.S., S.M., K.M., H.O., T.B., K.-i.M.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Soma Central Hospital (S.K.), Soma, Fukushima 976-0016, Japan; Institute of Reproductive and Developmental Biology (I.H.), Department of Surgery and Cancer, Imperial College London, London W12 0NN, United Kingdom; and Department of Physiology (I.H.), University of Turku, 20520 Turku, Finland.
authors.forename: Kanako
authors.initials: K
authors.lastname: Miyabayashi
authors.affiliation: Department of Molecular Biology (Y.S., S.M., K.M., H.O., T.B., K.-i.M.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Soma Central Hospital (S.K.), Soma, Fukushima 976-0016, Japan; Institute of Reproductive and Developmental Biology (I.H.), Department of Surgery and Cancer, Imperial College London, London W12 0NN, United Kingdom; and Department of Physiology (I.H.), University of Turku, 20520 Turku, Finland.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Otake
authors.affiliation: Department of Molecular Biology (Y.S., S.M., K.M., H.O., T.B., K.-i.M.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Soma Central Hospital (S.K.), Soma, Fukushima 976-0016, Japan; Institute of Reproductive and Developmental Biology (I.H.), Department of Surgery and Cancer, Imperial College London, London W12 0NN, United Kingdom; and Department of Physiology (I.H.), University of Turku, 20520 Turku, Finland.
authors.forename: Takashi
authors.initials: T
authors.lastname: Baba
authors.affiliation: Department of Molecular Biology (Y.S., S.M., K.M., H.O., T.B., K.-i.M.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Soma Central Hospital (S.K.), Soma, Fukushima 976-0016, Japan; Institute of Reproductive and Developmental Biology (I.H.), Department of Surgery and Cancer, Imperial College London, London W12 0NN, United Kingdom; and Department of Physiology (I.H.), University of Turku, 20520 Turku, Finland.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.affiliation: Department of Molecular Biology (Y.S., S.M., K.M., H.O., T.B., K.-i.M.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Soma Central Hospital (S.K.), Soma, Fukushima 976-0016, Japan; Institute of Reproductive and Developmental Biology (I.H.), Department of Surgery and Cancer, Imperial College London, London W12 0NN, United Kingdom; and Department of Physiology (I.H.), University of Turku, 20520 Turku, Finland.
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.affiliation: Department of Molecular Biology (Y.S., S.M., K.M., H.O., T.B., K.-i.M.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Soma Central Hospital (S.K.), Soma, Fukushima 976-0016, Japan; Institute of Reproductive and Developmental Biology (I.H.), Department of Surgery and Cancer, Imperial College London, London W12 0NN, United Kingdom; and Department of Physiology (I.H.), University of Turku, 20520 Turku, Finland.
authors.forename: Ken-ichirou
authors.initials: K
authors.lastname: Morohashi
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics; D007985:Leydig Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics*; D011974:Receptors, LH / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D054339:Steroidogenic Factor 1 / Q000235:genetics; D013737:Testis / Q000166:cytology / Q000196:embryology*; D013739:Testosterone / Q000378:metabolism
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D011974:Receptors, LH; D054339:Steroidogenic Factor 1; C485184:enhanced green fluorescent protein; C515058:steroidogenic factor 1, mouse; D049452:Green Fluorescent Proteins; D013739:Testosterone