Fate determination of fetal Leydig cells

Abstract

Leydig cell (LC) is one of the most important somatic cell types in testis, which localized in the interstitium between seminiferous tubules. The major function of Leydig cells is to produce steroid hormone, androgens. LC differentiation exhibits a biphasic pattern in rodent testes, which are divided into two different temporal mature populations, fetal Leydig cells (FLCs) and adult Leydig cells (ALCs). FLCs are transiently present in fetal testes and undergo involution or degeneration after birth. FLCs are completely devoid and replaced by ALCs in adult testes. Comparing to ALCs, FLCs display unique morphology, ultrastructure and functions. The origin of FLCs has been debated for many years, but it is still a mystery. Many factors have been reported regulating the specification, proliferation and differentiation of FLCs. FLCs degenerate in a few weeks postnatally, however, the underlying mechanism is still unknown. In this review, we will focus on the fate determination of FLCs, and summarize the resent progress on the morphology, ultrastructure, function, origin and involution of FLCs.

Keywords

fetal Leydig cells / adult Leydig cells / fate determination

References

[1] Angelova P, Davidoff M, Baleva K, Staykova M (1991). Substance P- and neuron-specific enolase-like immunoreactivity of rodent Leydig cells in tissue section and cell culture. Acta Histochem, 91(2): 131–139

[2] Baarends W M, Hoogerbrugge J W, Post M, Visser J A, De Rooij D G, Parvinen M, Themmen A P, Grootegoed J A (1995). Anti-mullerian hormone and anti-mullerian hormone type II receptor messenger ribonucleic acid expression during postnatal testis development and in the adult testis of the rat. Endocrinology, 136(12): 5614–5622

[3] Baarends W M, van Helmond M J, Post M, van der Schoot P J, Hoogerbrugge J W, de Winter J P, Uilenbroek J T, Karels B, Wilming L G, Meijers J H, (1994). A novel member of the transmembrane serine/threonine kinase receptor family is specifically expressed in the gonads and in mesenchymal cells adjacent to the müllerian duct. Development, 120(1): 189–197

[4] Baillie A H (1964). FURTHER OBSERVATIONS ON THE GROWTH AND HISTOCHEMISTRY OF LEYDIG TISSUE IN THE POSTNATAL PREPUBERTAL MOUSE TESTIS. J Anat, 98: 403–418

[5] Barsoum I B, Bingham N C, Parker K L, Jorgensen J S, Yao H H (2009). Activation of the Hedgehog pathway in the mouse fetal ovary leads to ectopic appearance of fetal Leydig cells and female pseudohermaphroditism. Dev Biol, 329(1): 96–103

[6] Barsoum I B, Yao H H (2010). Fetal Leydig cells: progenitor cell maintenance and differentiation. J Androl, 31(1): 11–15

[7] Behringer R R, Cate R L, Froelick G J, Palmiter R D, Brinster R L (1990). Abnormal sexual development in transgenic mice chronically expressing müllerian inhibiting substance. Nature, 345(6271): 167–170

[8] Behringer R R, Finegold M J, Cate R L (1994). Müllerian-inhibiting substance function during mammalian sexual development. Cell, 79(3): 415–425

[9] Betsholtz C, Raines E W (1997). Platelet-derived growth factor: a key regulator of connective tissue cells in embryogenesis and pathogenesis. Kidney Int, 51(5): 1361–1369

[10] Bitgood M J, McMahon A P (1995). Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev Biol, 172(1): 126–138

[11] Boström H, Willetts K, Pekny M, Levéen P, Lindahl P, Hedstrand H, Pekna M, Hellström M, Gebre-Medhin S, Schalling M, Nilsson M, Kurland S, Törnell J, Heath J K, Betsholtz C (1996). PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell, 85(6): 863–873

[12] Brennan J, Capel B (2004). One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet, 5(7): 509–521

[13] Brennan J, Tilmann C, Capel B (2003). Pdgfr-alpha mediates testis cord organization and fetal Leydig cell development in the XY gonad. Genes Dev, 17(6): 800–810

[14] Buehr M, Gu S, McLaren A (1993). Mesonephric contribution to testis differentiation in the fetal mouse. Development, 117(1): 273–281

[15] Chiwakata C, Brackmann B, Hunt N, Davidoff M, Schulze W, Ivell R (1991). Tachykinin (substance-P) gene expression in Leydig cells of the human and mouse testis. Endocrinology, 128(5): 2441–2448

[16] Cui S, Ross A, Stallings N, Parker K L, Capel B, Quaggin S E (2004). Disrupted gonadogenesis and male-to-female sex reversal in Pod1 knockout mice. Development, 131(16): 4095–4105

[17] Davidoff M S, Middendorff R, Müller D, Holstein A F, Müller D (2009). Fetal and Adult Leydig Cells Are of Common Orig. In The Neuroendocrine Leydig Cells and their Stem Cell Progenitors, the Pericytes. Berlin: Springer, pp. 89–103

[18] De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm J S, Schroeter E H, Schrijvers V, Wolfe M S, Ray W J, Goate A, Kopan R (1999). A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature, 398(6727): 518–522

[19] di Clemente N, Wilson C, Faure E, Boussin L, Carmillo P, Tizard R, Picard J Y, Vigier B, Josso N, Cate R (1994). Cloning, expression, and alternative splicing of the receptor for anti-Müllerian hormone. Mol Endocrinol, 8(8): 1006–1020

[20] Faria M J S, Simões Z L, Lunardi L O, Hartfelder K (2003). Apoptosis process in mouse Leydig cells during postnatal development. Microsc Microanal, 9(1): 68–73

[21] Gondos B, Morrison K P, Renston R H (1977). Leydig cell differentiation in the prepubertal rabbit testis. Biol Reprod, 17(5): 745–748

[22] Habert R, Lejeune H, Saez J M (2001). Origin, differentiation and regulation of fetal and adult Leydig cells. Mol Cell Endocrinol, 179(1-2): 47–74

[23] Haider S G (2004). Cell biology of Leydig cells in the testis. Int Rev Cytol, 233: 181–241

[24] Haider S G, Servos G, Tran N (2007). Structural and Histological Analysis of Leydig Cell Steroidogenic Function. In Payne A H, Hardy M P, eds. The Leydig Cell in Health and Disease. New Jersey: Humana Press, pp. 33–45

[25] Hatano O, Takakusu A, Nomura M, Morohashi K (1996). Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF-1. Genes Cells, 1(7): 663–671

[26] Huppert S S, Le A, Schroeter E H, Mumm J S, Saxena M T, Milner L A, Kopan R (2000). Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature, 405(6789): 966–970

[27] Kageyama R, Ohtsuka T, Kobayashi T (2007). The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development, 134(7): 1243–1251

[28] Karl J, Capel B (1998). Sertoli cells of the mouse testis originate from the coelomic epithelium. Dev Biol, 203(2): 323–333

[29] Karlsson L, Lindahl P, Heath J K, Betsholtz C (2000). Abnormal gastrointestinal development in PDGF-A and PDGFR-(alpha) deficient mice implicates a novel mesenchymal structure with putative instructive properties in villus morphogenesis. Development, 127(16): 3457–3466

[30] Kitamura K, Yanazawa M, Sugiyama N, Miura H, Iizuka-Kogo A, Kusaka M, Omichi K, Suzuki R, Kato-Fukui Y, Kamiirisa K, Matsuo M, Kamijo S, Kasahara M, Yoshioka H, Ogata T, Fukuda T, Kondo I, Kato M, Dobyns W B, Yokoyama M, Morohashi K (2002). Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet, 32(3): 359–369

[31] Lai E C (2004). Notch signaling: control of cell communication and cell fate. Development, 131(5): 965–973

[32] Lee M M, Donahoe P K (1993). Mullerian inhibiting substance: a gonadal hormone with multiple functions. Endocr Rev, 14(2): 152–164

[33] Lee M M, Seah C C, Masiakos P T, Sottas C M, Preffer F I, Donahoe P K, Maclaughlin D T, Hardy M P (1999). Müllerian-inhibiting substance type II receptor expression and function in purified rat Leydig cells. Endocrinology, 140(6): 2819–2827

[34] Lindahl P, Hellström M, Kalén M, Karlsson L, Pekny M, Pekna M, Soriano P, Betsholtz C (1998). Paracrine PDGF-B/PDGF-Rbeta signaling controls mesangial cell development in kidney glomeruli. Development, 125(17): 3313–3322

[35] Lording D W, De Kretser D M (1972). Comparative ultrastructural and histochemical studies of the interstitial cells of the rat testis during fetal and postnatal development. J Reprod Fertil, 29(2): 261–269

[36] Luo X, Ikeda Y, Parker K L (1994). A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell, 77(4): 481–490

[37] Martineau J, Nordqvist K, Tilmann C, Lovell-Badge R, Capel B (1997). Male-specific cell migration into the developing gonad. Curr Biol, 7(12): 958–968

[38] Mayerhofer A, Lahr G, Seidl K, Eusterschulte B, Christoph A, Gratzl M (1996). The neural cell adhesion molecule (NCAM) provides clues to the development of testicular Leydig cells. J Androl, 17(3): 223–230

[39] Mendis-Handagama S M, Ariyaratne H B (2001). Differentiation of the adult Leydig cell population in the postnatal testis. Biol Reprod, 65(3): 660–671

[40] Merchant-Larios H, Moreno-Mendoza N (1998). Mesonephric stromal cells differentiate into Leydig cells in the mouse fetal testis. Exp Cell Res, 244(1): 230–238

[41] Mishina Y, Rey R, Finegold M J, Matzuk M M, Josso N, Cate R L, Behringer R R (1996). Genetic analysis of the Müllerian-inhibiting substance signal transduction pathway in mammalian sexual differentiation. Genes Dev, 10(20): 2577–2587

[42] Niemi M, Kormano M (1964). CELL RENEWAL IN THE INTERSTITIAL TISSUE OF POSTNATAL PREPUBERAL RAT TESTIS. Endocrinology, 74(6): 996–998

[43] Nishino K, Yamanouchi K, Naito K, Tojo H (2001). Characterization of mesonephric cells that migrate into the XY gonad during testis differentiation. Exp Cell Res, 267(2): 225–232

[44] Racine C, Rey R, Forest M G, Louis F, Ferré A, Huhtaniemi I, Josso N, di Clemente N (1998). Receptors for anti-müllerian hormone on Leydig cells are responsible for its effects on steroidogenesis and cell differentiation. Proc Natl Acad Sci USA, 95(2): 594–599

[45] Roosen-Runge E C, Anderson D (1959). The development of the interstitial cells in the testis of the albino rat. Acta Anat (Basel), 37(1-2): 125–137

[46] Sadovsky Y, Crawford P A, Woodson K G, Polish J A, Clements M A, Tourtellotte L M, Simburger K, Milbrandt J (1995). Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proc Natl Acad Sci U S A, 92(24): 10939–10943

[47] Schmahl J, Eicher E M, Washburn L L, Capel B (2000). Sry induces cell proliferation in the mouse gonad. Development, 127(1): 65–73

[48] Schroeter E H, Kisslinger J A, Kopan R (1998). Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature, 393(6683): 382–386

[49] Soriano P (1994). Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev, 8(16): 1888–1896

[50] Tang H, Brennan J, Karl J, Hamada Y, Raetzman L, Capel B (2008). Notch signaling maintains Leydig progenitor cells in the mouse testis. Development, 135(22): 3745–3753

[51] Teixeira J, He W W, Shah P C, Morikawa N, Lee M M, Catlin E A, Hudson P L, Wing J, Maclaughlin D T, Donahoe P K (1996). Developmental expression of a candidate müllerian inhibiting substance type II receptor. Endocrinology, 137(1): 160–165

[52] Tilmann C, Capel B (1999). Mesonephric cell migration induces testis cord formation and Sertoli cell differentiation in the mammalian gonad. Development, 126(13): 2883–2890

[53] Yao H H, Capel B (2002). Disruption of testis cords by cyclopamine or forskolin reveals independent cellular pathways in testis organogenesis. Dev Biol, 246(2): 356–365

[54] Yao H H, Whoriskey W, Capel B (2002). Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes Dev, 16(11): 1433–1440

[55] Yao H H C, Barsoum I (2007). Fetal Leydig Cells. In: A HPayne, Hardy M P, eds. The Leydig Cell in Health and Disease. New Jersey: Humana Press, pp. 47–54

Acknowledgments

This study was supported by the National Basic Research Program of China (“973” project) (No. 2007CB947502), the CAS Innovation Project (No. KSCX2-YW-R-081) and the National Nature Science Foundation of China (Grant No. 31071271).

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