Desert hedgehog is a mammal-specific gene expressed during testicular and ovarian development in a marsupial

BMC Developmental Biology

Andrew J Pask²  Marilyn B Renfree²  Richard R Behringer⁴  Walid J Azar¹  William A O'Hara³ 

[1] Department of Zoology, The University of Melbourne, Victoria 3010, Australia;The Australian Research Council Centre of Excellence in Kangaroo Genomics, Australia;Department of Molecular and Cellular Biology, The University of Connecticut, Storrs CT 06269, USA;Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

关键词: Macropus eugenii.;    marsupial;    gene expression;    sexual differentiation;    Sex determination;   

Others  :  1086965
DOI  :  10.1186/1471-213X-11-72

 received in 2011-06-06, accepted in 2011-12-01,  发布年份 2011

【 摘 要 】

Background

Desert hedgehog (DHH) belongs to the hedgehog gene family that act as secreted intercellular signal transducers. DHH is an essential morphogen for normal testicular development and function in both mice and humans but is not present in the avian lineage. Like other hedgehog proteins, DHH signals through the patched (PTCH) receptors 1 and 2. Here we examine the expression and protein distribution of DHH, PTCH1 and PTCH2 in the developing testes of a marsupial mammal (the tammar wallaby) to determine whether DHH signalling is a conserved factor in gonadal development in all therian mammals.

Results

DHH, PTCH1 and PTCH2 were present in the marsupial genome and highly conserved with their eutherian orthologues. Phylogenetic analyses indicate that DHH has recently evolved and is a mammal-specific hedgehog orthologue. The marsupial PTCH2 receptor had an additional exon (exon 21a) not annotated in eutherian PTCH2 proteins. Interestingly we found evidence of this exon in humans and show that its translation would result in a truncated protein with functions similar to PTCH1. We also show that DHH expression was not restricted to the testes during gonadal development (as in mice), but was also expressed in the developing ovary. Expression of DHH, PTCH1 and PTCH2 in the adult tammar testis and ovary was consistent with findings in the adult mouse.

Conclusions

These data suggest that there is a highly conserved role for DHH signalling in the differentiation and function of the mammalian testis and that DHH may be necessary for marsupial ovarian development. The receptors PTCH1 and PTCH2 are highly conserved mediators of hedgehog signalling in both the developing and adult marsupial gonads. Together these findings indicate DHH is an essential therian mammal-specific morphogen in gonadal development and gametogenesis.

【 授权许可】

   
2011 O'Hara et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Bitgood MJ, Shen L, McMahon AP: Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr Biol 1996, 6:298-304.
• [2]Kamisago M, Kimura M, Furutani Y, Furutani M, Takao A, Momma K, Matsuoka R: Assignment of human desert hedgehog gene (DHH) to chromosome band 12q13.1 by in situ hybridization. Cytogenet Cell Genet 1999, 87:117-118.
• [3]Kumar S, Balczarek KA, Lai ZC: Evolution of the hedgehog gene family. Genetics 1996, 142:965-972.
• [4]Pathi S, Pagan-Westphal S, Baker DP, Garber EA, Rayhorn P, Bumcrot D, Tabin CJ, Blake Pepinsky R, Williams KP: Comparative biological responses to human Sonic, Indian, and Desert hedgehog. Mech Dev 2001, 106:107-117.
• [5]Tate G, Satoh H, Endo Y, Mitsuya T: Assignment of Desert Hedgehog (DHH) to human chromosome bands 12q12 - > q13.1 by in situ hybridization. Cytogenetics And Cell Genetics 2000, 88:93-94.
• [6]Ingham PW: Developmental biology - Boning up on Hedgehog's movements. Nature 1998, 394:16-17.
• [7]Mirsky R, Jessen KR: The neurobiology of Schwann cells. Brain Pathol 1999, 9:293-311.
• [8]Patten I, Placzek M: The role of Sonic hedgehog in neural tube patterning. Cellular And Molecular Life Sciences 2000, 57:1695-1708.
• [9]Perron M, Boy S, Amato MA, Viczian A, Koebernick K, Pieler T, Harris WA: A novel function for Hedgehog signalling in retinal pigment epithelium differentiation. Development 2003, 130:1565-1577.
• [10]Echelard Y, Epstein DJ, Stjacques B, Shen L, Mohler J, McMahon JA, McMahon AP: Sonic-Hedgehog, A Member Of A Family Of Putative Signaling Molecules, Is Implicated In The Regulation Of Cns Polarity. Cell 1993, 75:1417-1430.
• [11]van den Brink GR, Bleuming SA, Hardwick JC, Schepman BL, Offerhaus GJ, Keller JJ, Nielsen C, Gaffield W, van Deventer SJ, Roberts DJ, Peppelenbosch MP: Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. Nat Genet 2004, 36:277-282.
• [12]Spicer LJ, Sudo S, Aad PY, Wang LS, Chun SY, Ben-Shlomo I, Klein C, Hsueh AJ: The hedgehog-patched signaling pathway and function in the mammalian ovary: a novel role for hedgehog proteins in stimulating proliferation and steroidogenesis of theca cells. Reproduction 2009, 138:329-339.
• [13]Vortkamp A, Lee K, Lanske B, Segre GV, Kronenberg HM, Tabin CJ: Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 1996, 273:613-622.
• [14]Szczepny A, Hime GR, Loveland KL: Expression of hedgehog signalling components in adult mouse testis. Dev Dyn 2006, 235:3063-3070.
• [15]Mirsky R, Parmantier E, McMahon AP, Jessen KR: Schwann cell-derived desert hedgehog signals nerve sheath formation. Ann N Y Acad Sci 1999, 883:196-202.
• [16]Parmantier E, Lynn B, Lawson D, Turmaine M, Namini SS, Chakrabarti L, McMahon AP, Jessen KR, Mirsky R: Schwann cell-derived Desert hedgehog controls the development of peripheral nerve sheaths. Neuron 1999, 23:713-724.
• [17]Carpenter D, Stone DM, Brush J, Ryan A, Armanini M, Frantz G, Rosenthal A, de Sauvage FJ: Characterization of two patched receptors for the vertebrate hedgehog protein family. Proc Natl Acad Sci USA 1998, 95:13630-13634.
• [18]Rahnama F, Toftgard R, Zaphiropoulos PG: Distinct roles of PTCH2 splice variants in Hedgehog signalling. Biochem J 2004, 378:325-334.
• [19]Nusslein-Volhard C, Wieschause E: Mutation affecting segment number and polarity in Drosophila. Nature (london) 1980, 287:795-801.
• [20]Bitgood MJ, McMahon AP: Hedgehog And Bmp Genes Are Coexpressed At Many Diverse Sites Of Cell-Cell Interaction In The Mouse Embryo. Developmental Biology 1995, 172:126-138.
• [21]Bitgood MJ, Shen LY, McMahon AP: Sertoli cell signaling by Desert hedgehog regulates the male germline. Current Biology 1996, 6:298-304.
• [22]Sekido R, Lovell-Badge R: Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 2008, 453:930-934.
• [23]Clark AM, Garland KK, Russell LD: 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. Biology Of Reproduction 2000, 63:1825-1838.
• [24]Yao HH, Whoriskey W, Capel B: Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes Dev 2002, 16:1433-1440.
• [25]Barsoum IB, Bingham NC, Parker KL, Jorgensen JS, Yao HH: Activation of the Hedgehog pathway in the mouse fetal ovary leads to ectopic appearance of fetal Leydig cells and female pseudohermaphroditism. Dev Biol 2009, 329:96-103.
• [26]Russell MC, Cowan RG, Harman RM, Walker AL, Quirk SM: The hedgehog signaling pathway in the mouse ovary. Biol Reprod 2007, 77:226-236.
• [27]Umehara F, Tate G, Itoh K, Yamaguchi N, Douchi T, Mitsuya T, Osame M: A novel mutation of desert hedgehog in a patient with 46, XY partial gonadal dysgenesis accompanied by minifascicular neuropathy. Am J Hum Genet 2000, 67:1302-1305.
• [28]Canto P, Soderlund D, Reyes E, Mendez JP: Mutations in the Desert hedgehog (DHH) gene in patients with 46, XY complete pure gonadal dysgenesis (vol 89, pg 4480, 2004). Journal Of Clinical Endocrinology And Metabolism 2004, 89:5453-5453.
• [29]Bagheri-Fam S, Sinclair AH, Koopman P, Harley VR: Conserved regulatory modules in the Sox9 testis-specific enhancer predict roles for SOX, TCF/LEF, Forkhead, DMRT, and GATA proteins in vertebrate sex determination. Int J Biochem Cell Biol 2010, 42:472-477.
• [30]Bininda-Emonds OR, Cardillo M, Jones KE, MacPhee RD, Beck RM, Grenyer R, Price SA, Vos RA, Gittleman JL, Purvis A: The delayed rise of present-day mammals. Nature 2007, 446:507-512.
• [31]Renfree MB, Tyndale-Biscoe CH: Intrauterine development after diapause in the marsupial Macropus eugenii. Dev Biol 1973, 32:28-40.
• [32]Tyndale-Biscoe CH, Hearn JP, Renfree MB: Control of reproduction in macropodid marsupials. J Endocrinol 1974, 63:589-614.
• [33]O WS, Short RV, Renfree MB, Shaw G: Primary genetic control of somatic sexual differentiation in a mammal. Nature 1988, 331:716-717.
• [34]Harry JL, Koopman P, Brennan FE, Graves JA, Renfree MB: Widespread expression of the testis-determining gene SRY in a marsupial. Nat Genet 1995, 11:347-349.
• [35]Renfree MB, O WS, Short RV, Shaw G: Sexual differentiation of the urogenital system of the fetal and neonatal tammar wallaby, Macropus eugenii. Anat Embryol (Berl) 1996, 194:111-134.
• [36]Church GM, Gilbert W: Genomic sequencing. Proc Natl Acad Sci USA 1984, 81:1991-1995.
• [37]Chung JW, Pask AJ, Renfree MB: Seminiferous cord formation is regulated by Hedgehog signalling in the marsupial. Reproductive Biology 2011.
• [38]Renfree MB, Papenfuss AT, Deakin JE, Lindsay J, Heider T, Belov K, Rens W, Waters PD, Pharo EA, Shaw G, et al.: Genome sequence of an Australian kangaroo, Macropus eugenii, provides insight into the evolution of mammalian reproduction and development. Genome Biol 2011, 12:R81. BioMed Central Full Text
• [39]Schempp W, Meer B: Cytologic evidence for three human X-chromosomal segments escaping inactivation. Hum Genet 1983, 63:171-174.
• [40]Wilcox SA, Watson JM, Spencer JA, Graves JA: Comparative mapping identifies the fusion point of an ancient mammalian X-autosomal rearrangement. Genomics 1996, 35:66-70.
• [41]Pask AJ, Calatayud NE, Shaw G, Wood WG, Renfree MB: Estrogen blocks the nuclear entry of SOX9 in the developing gonad of a marsupial mammal. BMC Biology 2010, in press.
• [42]Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001, 29:e45.
• [43]Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP: Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 1993, 75:1417-1430.
• [44]Porter JA, Ekker SC, Park WJ, von Kessler DP, Young KE, Chen CH, Ma Y, Woods AS, Cotter RJ, Koonin EV, Beachy PA: Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell 1996, 86:21-34.
• [45]Lewis KE, Eisen JS: Hedgehog signaling is required for primary motoneuron induction in zebrafish. Development 2001, 128:3485-3495.
• [46]Musinova YR, Lisitsyna OM, Golyshev SA, Tuzhikov AI, Polyakov VY, Sheval EV: Nucleolar localization/retention signal is responsible for transient accumulation of histone H2B in the nucleolus through electrostatic interactions. Biochim Biophys Acta 2011, 1813:27-38.
• [47]Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R, Goodfellow PN: A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 1990, 346:240-244.
• [48]Motoyama J, Takabatake T, Takeshima K, Hui C: Ptch2, a second mouse Patched gene is co-expressed with Sonic hedgehog. Nat Genet 1998, 18:104-106.
• [49]Goodrich LV, Johnson RL, Milenkovic L, McMahon JA, Scott MP: Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev 1996, 10:301-312.