Mixed Signals: Development of the Testis

ABSTRACT

Induction and patterning of the testis occurs over a brief window of time. Before male-specific morphogenesis, the gonad primordium is bipotential and capable of developing into either an ovary or testis. However, expression of the transcription factor Sry initiates male development and induces patterning, proliferation, and epithelialization specific to the testis. Male sex determination begins with commitment of Sertoli cells via autonomous and nonautonomous mechanisms. These mechanisms have recently been shown to both promote the male fate and simultaneously repress ovarian development. A second critical event in the development of the testis is the epithelialization of testis cords. After their specification, Sertoli cells epithelialize and surround the male germ line to form large looping structures bound by extracellular matrix. Cells excluded from cord structures are called interstitial cells and comprise several different cell types, including steroidogenic cells, endothelial cells, and a smooth muscle cell that directly surround the cords. Numerous male-specific signaling pathways influence testis cord morphogenesis and specification of distinct cell types, although a coherent progression of events is unclear. In this article we focus on signals in the male gonad that first are responsible for the specification of Sertoli cells, and second for the specification and patterning of interstitial cells.

KEYWORDS

Sex determination - testis - organogenesis - growth factor signaling

REFERENCES

• 1 McLaren A. Primordial germ cells in the mouse.  Dev Biol. 2003;  262(1) 1-15
• 2 Bullejos M, Koopman P. Spatially dynamic expression of Sry in mouse genital ridges.  Dev Dyn. 2001;  221(2) 201-205
• 3 Koopman P, Munsterberg A, Capel B, Vivian N, Lovell-Badge R. Expression of a candidate sex-determining gene during mouse testis differentiation.  Nature. 1990;  348(6300) 450-452
• 4 Hacker A, Capel B, Goodfellow P, Lovell-Badge R. Expression of Sry, the mouse sex determining gene.  Development. 1995;  121(6) 1603-1614
• 5 Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R. Male development of chromosomally female mice transgenic for Sry .  Nature. 1991;  351(6322) 117-121
• 6 Canning C A, Lovell-Badge R. Sry and sex determination: how lazy can it be?.  Trends Genet. 2002;  18(3) 111-113
• 7 Ferrari S, Harley V R, Pontiggia A et al.. SRY, like HMG1, recognizes sharp angles in DNA.  EMBO J. 1992;  11(12) 4497-4506
• 8 Gubbay J, Collignon J, Koopman P et al.. A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes.  Nature. 1990;  346(6281) 216-217
• 9 Harley V R, Jackson D I, Hextall P J et al.. DNA binding activity of recombinant SRY from normal males and XY females.  Science. 1992;  255(5043) 453-456
• 10 Pontiggia A, Rimini R, Harley V R et al.. Sex-reversing mutations affect the architecture of SRY-DNA complexes.  EMBO J. 1994;  13(24) 6115-6124
• 11 Lovell-Badge R, Canning C, Sekido R. Sex-determining genes in mice: building pathways.  Novartis Found Symp. 2002;  244 4-18 discussion: 18-22 35-42 253-257
• 12 Kent J, Wheatley S C, Andrews J E, Sinclair A H, Koopman P. A male-specific role for SOX9 in vertebrate sex determination.  Development. 1996;  122(9) 2813-2822
• 13 Sekido R, Bar I, Narvaez V, Penny G, Lovell-Badge R. SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors.  Dev Biol. 2004;  274(2) 271-279
• 14 Morais da Silva S, Hacker A, Harley V et al.. Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds.  Nat Genet. 1996;  14(1) 62-68
• 15 Wagner T, Wirth J, Meyer J et al.. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9.  Cell. 1994;  79(6) 1111-1120
• 16 Qin Y, Bishop C E. Sox9 is sufficient for functional testis development producing fertile male mice in the absence of Sry .  Hum Mol Genet. 2005;  14(9) 1221-1229
• 17 Bishop C E, Whitworth D J, Qin Y et al.. A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse.  Nat Genet. 2000;  26(4) 490-494
• 18 Vidal V P, Chaboissier M C, de Rooij D G, Schedl A. Sox9 induces testis development in XX transgenic mice.  Nat Genet. 2001;  28(3) 216-217
• 19 Palmer S J, Burgoyne P S. In situ analysis of fetal, prepuberal and adult XX-XY chimaeric mouse testes: Sertoli cells are predominantly, but not exclusively, XY.  Development. 1991;  112(1) 265-268
• 20 Jeays-Ward K, Hoyle C, Brennan J et al.. Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad.  Development. 2003;  130(16) 3663-3670
• 21 Parma P, Radi O, Vidal V et al.. R-SPONDIN1 is essential in sex determination, skin differentiation and malignancy.  Nat Genet. 2006;  38(11) 1304-1309
• 22 Tomizuka K, Horikoshi K, Kitada R et al.. R-spondin1 plays an essential role in ovarian development through positively regulating WNT 4 signaling.  Hum Mol Genet. 2008;  , In press
• 23 Chassot A A, Ranc F, Gregoire E P et al.. Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary.  Hum Mol Genet. 2008;  17(9) 1264-1277
• 24 Binnerts M E, Kim K A, Bright J M et al.. R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6.  Proc Natl Acad Sci U S A. 2007;  104(37) 14700-14705
• 25 Wei Q, Yokota C, Semenov M V et al.. R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling.  J Biol Chem. 2007;  282(21) 15903-15911
• 26 Kim Y, Kobayashi A, Sekido R et al.. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination.  PLoS Biol. 2006;  4(6) e187
• 27 Itoh N. The Fgf families in humans, mice, and zebrafish: their evolutionary processes and roles in development, metabolism, and disease.  Biol Pharm Bull. 2007;  30(10) 1819-1825
• 28 Eswarakumar V P, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors.  Cytokine Growth Factor Rev. 2005;  16(2) 139-149
• 29 Colvin J S, Green R P, Schmahl J, Capel B, Ornitz D M. Male-to-female sex reversal in mice lacking fibroblast growth factor 9.  Cell. 2001;  104(6) 875-889
• 30 Schmahl J, Kim Y, Colvin J S, Ornitz D M, Capel B. Fgf9 induces proliferation and nuclear localization of FGFR2 in Sertoli precursors during male sex determination.  Development. 2004;  131(15) 3627-3636
• 31 Kim Y, Capel B. Balancing the bipotential gonad between alternative organ fates: a new perspective on an old problem.  Dev Dyn. 2006;  235(9) 2292-2300
• 32 Albrecht K H, Eicher E M. Evidence that Sry is expressed in pre-Sertoli cells and Sertoli and granulosa cells have a common precursor.  Dev Biol. 2001;  240(1) 92-107
• 33 Vainio S, Heikkila M, Kispert A, Chin N, McMahon A P. Female development in mammals is regulated by Wnt-4 signaling.  Nature. 1999;  397(6718) 405-409
• 34 Karl J, Capel B. Sertoli cells of the mouse testis originate from the coelomic epithelium.  Dev Biol. 1998;  203(2) 323-333
• 35 Wells A, Marti U. Signalling shortcuts: cell-surface receptors in the nucleus?.  Nat Rev Mol Cell Biol. 2002;  3(9) 697-702
• 36 Kim Y, Bingham N, Sekido R et al.. Fibroblast growth factor receptor 2 regulates proliferation and Sertoli differentiation during male sex determination.  Proc Natl Acad Sci U S A. 2007;  104(42) 16558-16563
• 37 Bagheri-Fam S, Sim H, Bernard P et al.. Loss of Fgfr2 leads to partial XY sex reversal.  Dev Biol. 2008;  314(1) 71-83
• 38 Chi L, Itaranta P, Zhang S, Vainio S. Sprouty2 is involved in male sex organogenesis by controlling fibroblast growth factor 9-induced mesonephric cell migration to the developing testis.  Endocrinology. 2006;  147(8) 3777-3788
• 39 Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow M A. Sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways.  Cell. 1998;  92(2) 253-263
• 40 Reich A, Sapir A, Shilo B. Sprouty is a general inhibitor of receptor tyrosine kinase signaling.  Development. 1999;  126(18) 4139-4147
• 41 Sasaki A, Taketomi T, Kato R et al.. Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to RAF1.  Nat Cell Biol. 2003;  5(5) 427-432
• 42 Brennan J, Tilmann C, Capel B. Pdgfr-alpha mediates testis cord organization and fetal Leydig cell development in the XY gonad.  Genes Dev. 2003;  17(6) 800-810
• 43 Adams I R, McLaren A. Sexually dimorphic development of mouse primordial germ cells: switching from oogenesis to spermatogenesis.  Development. 2002;  129(5) 1155-1164
• 44 Wilhelm D, Martinson F, Bradford S et al.. Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determination.  Dev Biol. 2005;  287(1) 111-124
• 45 Malki S, Nef S, Notarnicola C et al.. Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation.  EMBO J. 2005;  24(10) 1798-1809
• 46 Wilhelm D, Hiramatsu R, Mizusaki H et al.. SOX9 regulates prostaglandin D synthase gene transcription in vivo to ensure testis development.  J Biol Chem. 2007;  282(14) 10553-10560
• 47 Loftin C D, Tiano H F, Langenbach R. Phenotypes of the COX-deficient mice indicate physiological and pathophysiological roles for COX-1 and COX-2.  Prostaglandins Other Lipid Mediat. 2002;  68–69 177-185
• 48 Eguchi N, Minami T, Shirafuji N et al.. Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase-deficient mice.  Proc Natl Acad Sci U S A. 1999;  96(2) 726-730
• 49 Matsuoka T, Hirata M, Tanaka H et al.. Prostaglandin D2 as a mediator of allergic asthma.  Science. 2000;  287(5460) 2013-2017
• 50 Skinner M K, Fritz I B. Androgen stimulation of Sertoli cell function is enhanced by peritubular cells.  Mol Cell Endocrinol. 1985;  40(2–3) 115-122
• 51 Tung P S, Fritz I B. Interactions of Sertoli cells with myoid cells in vitro.  Biol Reprod. 1980;  23(1) 207-217
• 52 Tung P S, Fritz I B. Morphogenetic restructuring and formation of basement membranes by Sertoli cells and testis peritubular cells in co-culture: inhibition of the morphogenetic cascade by cyclic AMP derivatives and by blocking direct cell contact.  Dev Biol. 1987;  120(1) 139-153
• 53 Tilmann C, Capel B. Mesonephric cell migration induces testis cord formation and Sertoli cell differentiation in the mammalian gonad.  Development. 1999;  126(13) 2883-2890
• 54 Martineau J, Nordqvist K, Tilmann C, Lovell-Badge R, Capel B. Male-specific cell migration into the developing gonad.  Curr Biol. 1997;  7(12) 958-968
• 55 Jeanes A, Wilhelm D, Wilson M J et al.. Evaluation of candidate markers for the peritubular myoid cell lineage in the developing mouse testis.  Reproduction. 2005;  130(4) 509-516
• 56 Cool J, Carmunu F D, Szucsik J C, Capel B. Peritubular myoid cells are not the migrating population required for testis cord formation in the XY gonad.  Sxl Dev. 2008;  2 128-133
• 57 Brennan J, Karl J, Capel B. Divergent vascular mechanisms downstream of Sry establish the arterial system in the XY gonad.  Dev Biol. 2002;  244(2) 418-428
• 58 Gnessi L, Basciani S, Mariani S et al.. Leydig cell loss and spermatogenic arrest in platelet-derived growth factor (Pdgf)-A-deficient mice.  J Cell Biol. 2000;  149(5) 1019-1026
• 59 Clark A M, Garland K K, Russell L D. Desert hedgehog (Dhh) gene is required in the mouse testis for formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules.  Biol Reprod. 2000;  63(6) 1825-1838
• 60 Pierucci-Alves F, Clark A M, Russell L D. A developmental study of the Desert hedgehog-null mouse testis.  Biol Reprod. 2001;  65(5) 1392-1402
• 61 Bitgood M J, Shen L, McMahon A P. Sertoli cell signaling by Desert hedgehog regulates the male germline.  Curr Biol. 1996;  6(3) 298-304
• 62 Yao H H, Whoriskey W, Capel B. Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis.  Genes Dev. 2002;  16(11) 1433-1440
• 63 Yao H H, Capel B. Disruption of testis cords by cyclopamine or forskolin reveals independent cellular pathways in testis organogenesis.  Dev Biol. 2002;  246(2) 356-365
• 64 Levine E, Cupp A S, Skinner M K. Role of neurotropins in rat embryonic testis morphogenesis (cord formation).  Biol Reprod. 2000;  62(1) 132-142
• 65 Cupp A S, Kim G H, Skinner M K. Expression and action of neurotropin-3 and nerve growth factor in embryonic and early postnatal rat testis development.  Biol Reprod. 2000;  63(6) 1617-1628
• 66 Cupp A S, Uzumcu M, Skinner M K. Chemotactic role of neurotropin 3 in the embryonic testis that facilitates male sex determination.  Biol Reprod. 2003;  68(6) 2033-2037
• 67 Ross A J, Tilman C, Yao H, MacLaughlin D, Capel B. AMH induces mesonephric cell migration in XX gonads.  Mol Cell Endocrinol. 2003;  211(1–2) 1-7