Fetal Leydig cells (FLCs) and adult Leydig cells (ALCs) develop in the mammalian prenatal and postnatal testes, respectively. In mice, FLCs emerge in the interstitial space of the testis as early as embryonic day 12.5 and thereafter increase in number during the fetal stage. We previously established a transgenic mouse line in which FLCs are labeled with EGFP and demonstrated that the EGFP-labeled FLCs were present even in adult testes. However, the characteristics of FLCs during postnatal stages remained unclear. In the present study, a comparison of the transcriptomes of FLCs from prenatal and postnatal testes and of ALCs from adult testes revealed that FLCs gradually alter their characteristics across developmental stages and come to roughly resemble ALCs. Many cholesterogenic genes simultaneously expressed a unique alternation pattern, while many oxidative phosphorylation and β-oxidation (both mitochondrial functions) genes showed a different unique pattern. These metabolic gene expression alterations might be triggered by milieu changes, such as nutrient and oxygen supply, from the prenatal to the postnatal period.

Journal Section:
Editor's choice
Keywords:
Leydig cells, Metabolism, Gene expression, Steroidogenesis
1.
Baker PJ, Sha JA, McBride MW, Peng L, Payne AH, O'Shaughnessy PJ: Expression of 3β-hydroxysteroid dehydrogenase type I and type VI isoforms in the mouse testis during development. Eur J Biochem 260:911-917 (1999).
2.
Brennan J, Capel B: One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet 5:509-521 (2004).
3.
Brennan J, Tilmann C, Capel B: Pdgfr-α mediates testis cord organization and fetal Leydig cell development in the XY gonad. Genes Dev 17:800-810 (2003).
4.
Buaas FW, Gardiner JR, Clayton S, Val P, Swain A: In vivo evidence for the crucial role of SF1 in steroid-producing cells of the testis, ovary and adrenal gland. Development 139:4561-4570 (2012).
5.
Cui S, Ross A, Stallings N, Parker KL, Capel B, Quaggin SE: Disrupted gonadogenesis and male-to-female sex reversal in Pod1 knockout mice. Development 131:4095-4105 (2004).
6.
Griswold SL, Behringer RR: Fetal Leydig cell origin and development. Sex Dev 3:1-15 (2009).
7.
Hatano O, Takakusu A, Nomura M, Morohashi K: Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF-1. Genes Cells 1:663-671 (1996).
8.
Heymann MA, Rudolph AM: Effects of congenital heart disease on fetal and neonatal circulations. Prog Cardiovasc Dis 15:115-143 (1972).
9.
Huhtaniemi I, Pelliniemi LJ: Fetal Leydig cells: cellular origin, morphology, life span, and special functional features. Proc Soc Exp Biol Med 201:125-140 (1992).
10.
Inoue M, Shima Y, Miyabayashi K, Tokunaga K, Sato T, Baba T, et al: Isolation and characterization of fetal Leydig progenitor cells of male mice. Endocrinology 157:1222-1233 (2016).
11.
Jameson SA, Natarajan A, Cool J, DeFalco T, Maatouk DM, et al: Temporal transcriptional profiling of somatic and germ cells reveals biased lineage priming of sexual fate in the fetal mouse gonad. PLoS Genet 8:e1002575 (2012).
12.
Kerr JB, Knell CM: The fate of fetal Leydig cells during the development of the fetal and postnatal rat testis. Development 103:535-544 (1988).
13.
Kuopio T, Tapanainen J, Pelliniemi LJ, Huhtaniemi I: Developmental stages of fetal-type Leydig cells in prepubertal rats. Development 107:213-220 (1989).
14.
Macleod DJ, Sharpe RM, Welsh M, Fisken M, Scott HM, et al: Androgen action in the masculinization programming window and development of male reproductive organs. Int J Androl 33:279-287 (2010).
15.
McClelland KS, Bell K, Larney C, Harley VR, Sinclair AH, et al: Purification and transcriptomic analysis of mouse fetal Leydig cells reveals candidate genes for specification of gonadal steroidogenic cells. Biol Reprod 92:145 (2015).
16.
McDowell EN, Kisielewski AE, Pike JW, Franco HL, Yao HH, Johnson KJ: A transcriptome-wide screen for mRNAs enriched in fetal Leydig cells: CRHR1 agonism stimulates rat and mouse fetal testis steroidogenesis. PLoS One 7:e47359 (2012).
17.
Meeks JJ, Crawford SE, Russell TA, Morohashi K, Weiss J, Jameson JL: Dax1 regulates testis cord organization during gonadal differentiation. Development 130:1029-1036 (2003).
18.
Miyabayashi K, Katoh-Fukui Y, Ogawa H, Baba T, Shima Y, et al: Aristaless related homeobox gene, Arx, is implicated in mouse fetal Leydig cell differentiation possibly through expressing in the progenitor cells. PLoS One 8:e68050 (2013).
19.
Miyabayashi K, Tokunaga K, Otake H, Baba T, Shima Y, Morohashi K: Heterogeneity of ovarian theca and interstitial gland cells in mice. PLoS One 10:e0128352 (2015).
20.
O'Shaughnessy PJ, Baker PJ, Heikkilä M, Vainio S, McMahon AP: Localization of 17β- hydroxysteroid dehydrogenase/17-ketosteroid reductase isoform expression in the developing mouse testis - androstenedione is the major androgen secreted by fetal/neonatal Leydig cells. Endocrinology 141:2631-2637 (2000).
21.
O'Shaughnessy PJ, Willerton L, Baker PJ: Changes in Leydig cell gene expression during development in the mouse. Biol Reprod 66:966-975 (2002).
22.
Santos AC, Lehmann R: Isoprenoids control germ cell migration downstream of HMGCoA reductase. Dev Cell 6:283-293 (2004).
23.
Schönenberger MJ, Kovacs WJ: Hypoxia signaling pathways: modulators of oxygen-related organelles. Front Cell Dev Biol 3:42 (2015).
24.
SEQC/MAQC-III Consortium: A comprehensive assessment of RNA-seq accuracy, reproducibility and information content by the Sequencing Quality Control Consortium. Nat Biotechnol 32:903-914 (2014).
25.
Sharpe RM, Maddocks S, Kerr JB: Cell-cell interactions in the control of spermatogenesis as studied using Leydig cell destruction and testosterone replacement. Am J Anat 188:3-20 (1990).
26.
Shima Y, Miyabayashi K, Baba T, Otake H, Katsura Y, et al: Identification of an enhancer in the Ad4BP/SF-1 gene specific for fetal Leydig cells. Endocrinology 153:417-425 (2012).
27.
Shima Y, Miyabayashi K, Haraguchi S, Arakawa T, Otake H, et al: Contribution of Leydig and Sertoli cells to testosterone production in mouse fetal testes. Mol Endocrinol 27:63-73 (2013).
28.
Shima Y, Matsuzaki S, Miyabayashi K, Otake H, Baba T, et al: Fetal Leydig cells persist as an androgen-independent subpopulation in the postnatal testis. Mol Endocrinol 29:1581-1593 (2015).
29.
Svingen T, Koopman P: Building the mammalian testis: origins, differentiation, and assembly of the component cell populations. Genes Dev 27:2409-2426 (2013).
30.
Tang H, Brennan J, Karl J, Hamada Y, Raetzman L, Capel B: Notch signaling maintains Leydig progenitor cells in the mouse testis. Development 135:3745-3753 (2008).
31.
Teerds KJ, Huhtaniemi IT: Morphological and functional maturation of Leydig cells: from rodent models to primates. Hum Reprod Update 21:310-328 (2015).
32.
Tricarico PM, Crovella S, Celsi F: Mevalonate pathway blockade, mitochondrial dysfunction and autophagy: a possible link. Int J Mol Sci 16:16067-16084 (2015).
33.
van den Driesche S, Walker M, McKinnell C, Scott HM, Eddie SL, et al: Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents. PLoS One 7:e37064 (2012).
34.
Wang RS, Yeh S, Tzeng CR, Chang C: Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell-specific androgen receptor knockout mice. Endocr Rev 30:119-132 (2009).
35.
Yao HH, Whoriskey W, Capel B: Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes Dev 16:1433-1440 (2002).
© 2016 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2016
You do not currently have access to this content.