Mixed Signals: Development of the Testis

 

 Buy Article Permissions and Reprints

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.

REFERENCES

• 1 McLaren A. Primordial germ cells in the mouse.  Dev Biol. 2003;  262(1) 1-15
  CrossrefPubMedGoogle Scholar
• 2 Bullejos M, Koopman P. Spatially dynamic expression of Sry in mouse genital ridges.  Dev Dyn. 2001;  221(2) 201-205
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 4 Hacker A, Capel B, Goodfellow P, Lovell-Badge R. Expression of Sry, the mouse sex determining gene.  Development. 1995;  121(6) 1603-1614
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 6 Canning C A, Lovell-Badge R. Sry and sex determination: how lazy can it be?.  Trends Genet. 2002;  18(3) 111-113
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 28 Eswarakumar V P, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors.  Cytokine Growth Factor Rev. 2005;  16(2) 139-149
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 34 Karl J, Capel B. Sertoli cells of the mouse testis originate from the coelomic epithelium.  Dev Biol. 1998;  203(2) 323-333
  CrossrefPubMedGoogle Scholar
• 35 Wells A, Marti U. Signalling shortcuts: cell-surface receptors in the nucleus?.  Nat Rev Mol Cell Biol. 2002;  3(9) 697-702
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 40 Reich A, Sapir A, Shilo B. Sprouty is a general inhibitor of receptor tyrosine kinase signaling.  Development. 1999;  126(18) 4139-4147
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 49 Matsuoka T, Hirata M, Tanaka H et al.. Prostaglandin D2 as a mediator of allergic asthma.  Science. 2000;  287(5460) 2013-2017
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 51 Tung P S, Fritz I B. Interactions of Sertoli cells with myoid cells in vitro.  Biol Reprod. 1980;  23(1) 207-217
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar

Dr. Blanche Capel

The Department of Cell Biology, Duke University Medical Center, Box 3471

Genome Science Research Building II, Room 4026, Research Drive, Duke University, Durham, NC 27710

Email: b.capel@cellbio.duke.edu