The study of the external genitalia is divided into 2 developmental stages: the formation and growth of a bipotential genital tubercle (GT) and the sexual differentiation of the male and female GT. The sexually dimorphic processes, which occur during the second part of GT differentiation, are suggested to be governed by androgen signaling and more recently crosstalk with other signaling factors. The process of elucidating the regulatory mechanisms of hormone signaling towards other signaling networks in the GT is still in its early stages. Nevertheless, it is becoming a productive area of research. This review summarizes various studies on the development of the murine GT and the defining characteristics of a masculinized GT and presents the different signaling pathways possibly involved during masculinization.

Keywords:
Androgen, External genitalia development, Genital tubercle, Growth factor signaling, Hormone signaling, Sonic hedgehog, WNT/CTNNB1
1.
Anderson CA, Clark RL: External genitalia of the rat: normal development and the histogenesis of 5 alpha-reductase inhibitor-induced abnormalities. Teratology 42:483-496 (1990).
2.
Baskin LS: Hypospadias and urethral development. J Urol 163:951-956 (2000).
3.
Baskin LS: Hypospadias and Genital Development (Kluwer Academic/Plenum Publishers, New York 2004).
4.
Baskin LS, Erol A, Li YW, Cunha GR: Anatomical studies of hypospadias. J Urol 160:1108-1115 (1998).
5.
Beleza-Meireles A, Kockum I, Lundberg F, Söderhäll C, Nordenskjöld A: Risk factors for hypospadias in the estrogen receptor 2 gene. J Clin Endocrinol Metab 92:3712-3718 (2007a).
6.
Beleza-Meireles A, Lundberg F, Lagerstedt K, Zhou X, Omrani D, et al: FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias. Eur J Hum Genet 15:405-410 (2007b).
7.
Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, et al: Genetic evidence equating SRY and the testis-determining factor. Nature 348:448-450 (1990).
8.
Cambray N, Wilson V: Two distinct sources for a population of maturing axial progenitors. Development 134:2829-2840 (2007).
9.
Capel B: The battle of the sexes. Mech Dev 92:89-103 (2000).
10.
Chambon C, Duteil D, Vignaud A, Ferry A, Messaddeq N, et al: Myocytic androgen receptor controls the strength but not the mass of limb muscles. Proc Natl Acad Sci USA 107:14327-14332 (2010).
11.
Chen Y, Zajac JD, MacLean HE: Androgen regulation of satellite cell function. J Endocrinol 186:21-31 (2005).
12.
Chesire DR, Isaacs WB: Ligand-dependent inhibition of beta-catenin/TCF signaling by androgen receptor. Oncogene 21:8453-8469 (2002).
13.
Chesire DR, Ewing CM, Gage WR, Isaacs WB: In vitro evidence for complex modes of nuclear beta-catenin signaling during prostate growth and tumorigenesis. Oncogene 21:2679-2694 (2002).
14.
Cheung-Flynn J, Prapapanich V, Cox MB, Riggs DL, Suarez-Quian C, Smith DF: Physiological role for the cochaperone FKBP52 in androgen receptor signaling. Mol Endocrinol 19:1654-1666 (2005).
15.
Chung JW, Pask AJ, Renfree MB: Seminiferous cord formation is regulated by hedgehog signaling in the marsupial. Biol Reprod 86:80 (2012).
16.
Ciani L, Salinas PC: c-Jun N-terminal kinase (JNK) cooperates with Gsk3beta to regulate Dishevelled-mediated microtubule stability. BMC Cell Biol 8:27 (2007).
17.
Clark RL, Antonello JM, Grossman SJ, Wise LD, Anderson C, et al: External genitalia abnormalities in male rats exposed in utero to finasteride, a 5 alpha-reductase inhibitor. Teratology 42:91-100 (1990).
18.
Clemens LG, Gladue BA, Coniglio LP: Prenatal endogenous androgenic influences on masculine sexual behavior and genital morphology in male and female rats. Horm Behav 10:40-53 (1978).
19.
Couse JF, Korach KS: Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 20:358-417 (1999).
20.
Dravis C, Yokoyama N, Chumley MJ, Cowan CA, Silvany RE, et al: Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development. Dev Biol 271:272-290 (2004).
21.
Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, et al: Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75:1417-1430 (1993).
22.
Eggers S, Sinclair A: Mammalian sex determination - insights from humans and mice. Chromosome Res 20:215-238 (2012).
23.
Eisenberg ML, Hsieh T-C, Pastuszak AW, McIntyre MG, Walters RC, et al: The relationship between anogenital distance and the androgen receptor CAG repeat length. Asian J Androl 15:286-289 (2013).
24.
Escobar LF, Heiman M, Zimmer D, Careskey H: Urorectal septum malformation sequence: prenatal progression, clinical report, and embryology review. Am J Med Genet A 143A:2722-2726 (2007).
25.
Febbo PG, Lowenberg M, Thorner AR, Brown M, Loda M, Golub TR: Androgen mediated regulation and functional implications of fkbp51 expression in prostate cancer. J Urol 173:1772-1777 (2005).
26.
Franco HL, Yao HH-C: Sex and hedgehog: roles of genes in the hedgehog signaling pathway in mammalian sexual differentiation. Chromosome Res 20:247-258 (2012).
27.
Garcia-Barceló M-M, Wong KK-Y, Lui VC-H, Yuan Z-W, So M-T, et al: Identification of a HOXD13 mutation in a VACTERL patient. Am J Med Genet A 146A:3181-3185 (2008).
28.
Garrido-Allepuz C, González-Lamuño D, Ros MA: Sirenomelia phenotype in bmp7;shh compound mutants: a novel experimental model for studies of caudal body malformations. PLoS One 7:e44962 (2012).
29.
Gnanapragasam VJ, Robson CN, Neal DE, Leung HY: Regulation of FGF8 expression by the androgen receptor in human prostate cancer. Oncogene 21:5069-5080 (2002).
30.
Gray H: Anatomy of the Human Body (Lea & Febiger, Philadelphia 1918).
31.
Gray LE Jr, Ostby J, Furr J, Price M, Veeramachaneni DN, Parks L: Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol Sci 58:350-365 (2000).
32.
Gray LE Jr, Ostby J, Furr J, Wolf CJ, Lambright C, et al: Effects of environmental antiandrogens on reproductive development in experimental animals. Hum Reprod Update 7:248-264 (2001).
33.
Gubbay J, Collignon J, Koopman P, Capel B, Economou A, 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 346:245-250 (1990).
34.
Gupta A, Ketchum N, Roehrborn CG, Schecter A, Aragaki CC, Michalek JE: Serum dioxin, testosterone, and subsequent risk of benign prostatic hyperplasia: a prospective cohort study of Air Force veterans. Environ Health Perspect 114:1649-1654 (2006).
35.
Haraguchi R, Suzuki K, Murakami R, Sakai M, Kamikawa M, et al: Molecular analysis of external genitalia formation: the role of fibroblast growth factor (Fgf) genes during genital tubercle formation. Development 127:2471-2479 (2000).
36.
Haraguchi R, Mo R, Hui C, Motoyama J, Makino S, et al: Unique functions of Sonic hedgehog signaling during external genitalia development. Development 128:4241-4250 (2001).
37.
Haraguchi R, Motoyama J, Sasaki H, Satoh Y, Miyagawa S, et al: Molecular analysis of coordinated bladder and urogenital organ formation by Hedgehog signaling. Development 134:525-533 (2007).
38.
Haraguchi R, Matsumaru D, Nakagata N, Miyagawa S, Suzuki K, et al: The hedgehog signal induced modulation of bone morphogenetic protein signaling: an essential signaling relay for urinary tract morphogenesis. PLoS One 7:e42245 (2012).
39.
Hassoun R, Schwartz P, Rath D, Viebahn C, Männer J: Germ layer differentiation during early hindgut and cloaca formation in rabbit and pig embryos. J Anat 217:665-678 (2010).
40.
Hiort O: The differential role of androgens in early human sex development. BMC Med 11:152 (2013).
41.
Hsiao PW, Thin TH, Lin DL, Chang C: Differential regulation of testosterone vs. 5alpha-dihydrotestosterone by selective androgen response elements. Mol Cell Biochem 206:169-175 (2000).
42.
Hynes PJ, Fraher JP: The development of the male genitourinary system: II. The origin and formation of the urethral plate. Br J Plast Surg 57:112-121 (2004).
43.
Imai Y, Youn M-Y, Inoue K, Takada I, Kouzmenko A, Kato S: Nuclear receptors in bone physiology and diseases. Physiol Rev 93:481-523 (2013).
44.
Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE: Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 186:1213-1215 (1974).
45.
Imperato-McGinley J, Peterson RE, Gautier T, Sturla E: Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5alpha-reductase deficiency. N Engl J Med 300:1233-1237 (1979).
46.
Inawaka K, Kishimoto N, Higuchi H, Kawamura S: Maternal exposure to procymidone has no effects on fetal external genitalia development in male rabbit fetuses in a modified developmental toxicity study. J Toxicol Sci 35:299-307 (2010).
47.
Jacob DA, Ray T, Bengston CL, Lindsten T, Wu J, et al: The role of cell death in sexually dimorphic muscle development: male-specific muscles are retained in female bax/bak knockout mice. Dev Neurobiol 68:1303-1314 (2008).
48.
Kaftanovskaya EM, Huang Z, Barbara AM, De Gendt K, Verhoeven G, et al: Cryptorchidism in mice with an androgen receptor ablation in gubernaculum testis. Mol Endocrinol 26:598-607 (2012).
49.
Karacan I, Aslan C, Hirshkowitz M: Erectile mechanisms in man. Science 220:1080-1082 (1983).
50.
Kaufman MH, Bard JBL: The Anatomical Basis of Mouse Development (Academic Press, San Diego 1999).
51.
Kondo T, Zákány J, Innis JW, Duboule D: Of fingers, toes and penises. Nature 390:29 (1997).
52.
Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R: Male development of chromosomally female mice transgenic for Sry. Nature 351:117-121 (1991).
53.
Korach KS, Couse JF, Curtis SW, Washburn TF, Lindzey J, et al: Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes. Recent Prog Horm Res 51:159-186 (1996).
54.
Koster MI, Kim S, Mills AA, DeMayo FJ, Roop DR: p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev 18:126-131 (2004).
55.
Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, et al: Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci USA 95:15677-15682 (1998).
56.
Kypta RM, Waxman J: Wnt/β-catenin signalling in prostate cancer. Nat Rev Urol (2012), E-pub ahead of print.
57.
Labrie F, Sugimoto Y, Luu-The V, Simard J, Lachance Y, et al: Structure of human type II 5 alpha-reductase gene. Endocrinology 131:1571-1573 (1992).
58.
Lee DK: Androgen receptor enhances myogenin expression and accelerates differentiation. Biochem Biophys Res Commun 294:408-413 (2002).
59.
Li J, Willingham E, Baskin LS: Gene expression profiles in mouse urethral development. BJU Int 98:880-885 (2006).
60.
Lin C, Yin Y, Long F, Ma L: Tissue-specific requirements of beta-catenin in external genitalia development. Development 135:2815-2825 (2008).
61.
Lin C, Yin Y, Veith GM, Fisher AV, Long F, Ma L: Temporal and spatial dissection of Shh signaling in genital tubercle development. Development 136:3959-3967 (2009).
62.
Lin C, Yin Y, Bell SM, Veith GM, Chen H, et al: Delineating a conserved genetic cassette promoting outgrowth of body appendages. PLoS Genet 9:e1003231 (2013).
63.
Lorenzo AJ, Nguyen MT, Sozubir S, Henkemeyer M, Baker LA: Dihydrotestesterone induction of EPHB2 expression in the female genital tubercle mimics male pattern of expression during embryogenesis. J Urol 170:1618-1623 (2003).
64.
Lyon MF, Hawkes SG: X-linked gene for testicular feminization in the mouse. Nature 227:1217-1219 (1970).
65.
MacLean HE, Chiu WSM, Notini AJ, Axell A-M, Davey RA, et al: Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice. FASEB J 22:2676-2689 (2008).
66.
Mahendroo MS, Cala KM, Russell DW: 5 alpha-reduced androgens play a key role in murine parturition. Mol Endocrinol 10:380-392 (1996).
67.
Maitah MY, Ali S, Ahmad A, Gadgeel S, Sarkar FH: Up-Regulation of sonic hedgehog contributes to TGF-β1-induced epithelial to mesenchymal transition in NSCLC cells. PLoS One 6:e16068 (2011).
68.
Matsumaru D, Haraguchi R, Miyagawa S, Motoyama J, Nakagata N, et al: Genetic analysis of Hedgehog signaling in ventral body wall development and the onset of omphalocele formation. PLoS One 6:e16260 (2011).
69.
Mazahery AR, Suzuki K, Nagafuchi A, Miyajima M, Nakagata N, et al: Functional analysis of ectodermal β-catenin during external genitalia formation. Congenit Anom 53:34-41 (2013).
70.
McPhaul MJ, Marcelli M, Zoppi S, Griffin JE, Wilson JD: Genetic basis of endocrine disease. 4. The spectrum of mutations in the androgen receptor gene that causes androgen resistance. J Clin Endocrinol Metab 76:17-23 (1993).
71.
Miyagawa S, Moon A, Haraguchi R, Inoue C, Harada M, et al: Dosage-dependent hedgehog signals integrated with Wnt/beta-catenin signaling regulate external genitalia formation as an appendicular program. Development 136:3969-3978 (2009a).
72.
Miyagawa S, Satoh Y, Haraguchi R, Suzuki K, Iguchi T, et al: Genetic interactions of the androgen and Wnt/beta-catenin pathways for the masculinization of external genitalia. Mol Endocrinol 23:871-880 (2009b).
73.
Miyagawa S, Matsumaru D, Murashima A, Omori A, Satoh Y, et al: The role of sonic hedgehog-Gli2 pathway in the masculinization of external genitalia. Endocrinology 152:2894-2903 (2011).
74.
Miyagawa S, Masayo H, Matsumaru D, Tanaka K, Inoue C, et al: Disruption of the temporally regulated cloaca endodermal B-catenin signaling causes anorectal malformations. Cell Death Differ, in press.
75.
Morohashi K, Baba T, Tanaka M: Steroid hormones and the development of reproductive organs. Sex Dev 7:61-79 (2013).
76.
Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC: Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know? Endocr Rev 26:898-915 (2005).
77.
Murakami R: A histological study of the development of the penis of wild-type and androgen-insensitive mice. J Anat 153:223-231 (1987).
78.
Murashima A, Miyagawa S, Ogino Y, Nishida-Fukuda H, Araki K, et al: Essential roles of androgen signaling in Wolffian duct stabilization and epididymal cell differentiation. Endocrinology 152:1640-1651 (2011).
79.
Nikolova G, Vilain E: Mechanisms of disease: Transcription factors in sex determination - relevance to human disorders of sex development. Nat Clin Pract Endocrinol Metab 2:231-238 (2006).
80.
Nishida H, Miyagawa S, Matsumaru D, Wada Y, Satoh Y, et al: Gene expression analyses on embryonic external genitalia: identification of regulatory genes possibly involved in masculinization processes. Congenit Anom 48:63-67 (2008).
81.
Ogino Y, Miyagawa S, Katoh H, Prins GS, Iguchi T, Yamada G: Essential functions of androgen signaling emerged through the developmental analysis of vertebrate sex characteristics. Evol Dev 13:315-325 (2011).
82.
Omori A, Harada M, Ohta S, Villacorte M, Sugimura Y, et al: Epithelial Bmp (Bone morphogenetic protein) signaling for bulbourethral gland development: a mouse model for congenital cystic dilation. Congenit Anom 51:102-109 (2011).
83.
Pask AJ: A role for estrogen in somatic cell fate of the mammalian gonad. Chromosome Res 20:239-245 (2012).
84.
Pask AJ, Kanasaki H, Kaiser UB, Conn PM, Janovick JA, et al: A novel mouse model of hypogonadotrophic hypogonadism: N-ethyl-N-nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation. Mol Endocrinol 19:972-981 (2005).
85.
Perriton CL, Powles N, Chiang C, Maconochie MK, Cohn M: Sonic hedgehog signaling from the urethral epithelium controls external genital development. Dev Biol 247:26-46 (2002).
86.
Peterson RE, Imperato-McGinley J, Gautier T, Sturla E: Male pseudohermaphroditism due to steroid 5-alpha-reductase deficiency. Am J Med 62:170-191 (1977).
87.
Petiot A, Perriton CL, Dickson C, Cohn MJ: Development of the mammalian urethra is controlled by Fgfr2-IIIb. Development 132:2441-2450 (2005).
88.
Podkowa M, Zhao X, Chow C-W, Coffey ET, Davis RJ, Attisano L: Microtubule stabilization by bone morphogenetic protein receptor-mediated scaffolding of c-Jun N-terminal kinase promotes dendrite formation. Mol Cell Biol 30:2241-2250 (2010).
89.
Podlasek CA, Zelner DJ, Jiang HB, Tang Y, Houston J, et al: Sonic hedgehog cascade is required for penile postnatal morphogenesis, differentiation, and adult homeostasis. Biol Reprod 68:423-438 (2003).
90.
Qiao L, Tasian GE, Zhang H, Cunha GR, Baskin LS: ZEB1 is estrogen responsive in vitro in human foreskin cells and is over expressed in penile skin in patients with severe hypospadias. J Urol 185:1888-1893 (2011).
91.
Renfree MB, Fenelon J, Wijiyanti G, Wilson JD, Shaw G: Wolffian duct differentiation by physiological concentrations of androgen delivered systemically. Dev Biol 334:429-436 (2009).
92.
Rodriguez E Jr, Weiss DA, Ferretti M, Wang H, Menshenia J, et al: Specific morphogenetic events in mouse external genitalia sex differentiation are responsive/dependent upon androgens and/or estrogens. Differentiation 84:269-279 (2012).
93.
Sachs BD: Role of striated penile muscles in penile reflexes, copulation, and induction of pregnancy in the rat. J Reprod Fertil 66:433-443 (1982).
94.
Sato T, Matsumoto T, Kawano H, Watanabe T, Uematsu Y, et al: Brain masculinization requires androgen receptor function. Proc Natl Acad Sci USA 101:1673-1678 (2004).
95.
Satoh Y, Haraguchi R, Wright TJ, Mansour SL, Partanen J, et al: Regulation of external genitalia development by concerted actions of FGF ligands and FGF receptors. Anat Embryol 208:479-486 (2004).
96.
Seifert AW, Harfe BD, Cohn M: Cell lineage analysis demonstrates an endodermal origin of the distal urethra and perineum. Dev Biol 318:143-152 (2008).
97.
Seifert AW, Yamaguchi T, Cohn MJ: Functional and phylogenetic analysis shows that Fgf8 is a marker of genital induction in mammals but is not required for external genital development. Development 136:2643-2651 (2009).
98.
Seifert AW, Zheng Z, Ormerod BK, Cohn MJ: Sonic hedgehog controls growth of external genitalia by regulating cell cycle kinetics. Nat Commun 1:23 (2010).
99.
Sissung TM, Price DK, Sparreboom A, Figg WD: Pharmacogenetics and regulation of human cytochrome P450 1B1: implications in hormone-mediated tumor metabolism and a novel target for therapeutic intervention. Mol Cancer Res 4:135-150 (2006).
100.
Stadler HS: Modelling genitourinary defects in mice: an emerging genetic and developmental system. Nat Rev Genet 4:478-482 (2003).
101.
Suzuki K, Ogino Y, Murakami R, Satoh Y, Bachiller D, Yamada G: Embryonic development of mouse external genitalia: insights into a unique mode of organogenesis. Evol Dev 4:133-141 (2002).
102.
Suzuki K, Bachiller D, Chen YP, Kamikawa M, Ogi H, et al: Regulation of outgrowth and apoptosis for the terminal appendage: external genitalia development by concerted actions of BMP signaling [corrected]. Development 130:6209-6220 (2003).
103.
Suzuki K, Haraguchi R, Ogata T, Barbieri O, Alegria O, et al: Abnormal urethra formation in mouse models of split-hand/split-foot malformation type 1 and type 4. Eur J Hum Genet 16:36-44 (2008).
104.
Suzuki K, Adachi Y, Numata T, Nakada S, Yanagita M, et al: Reduced BMP signaling results in hindlimb fusion with lethal pelvic/urogenital organ aplasia: a new mouse model of sirenomelia. PLoS One 7:e43453 (2012).
105.
Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, et al: Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 113:1056-1061 (2005).
106.
Tanaka A, Miyamoto K, Minamino N, Takeda M, Sato B, et al: Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mouse mammary carcinoma cells. Proc Natl Acad Sci USA 89:8928-8932 (1992).
107.
Wallach SJ, Hart BL: The role of the striated penile muscles of the male rat in seminal plug dislodgement and deposition. Physiol Behav 31:815-821 (1983).
108.
Wang C, Gargollo P, Guo C, Tang T, Mingin G, et al: Six1 and Eya1 are critical regulators of peri-cloacal mesenchymal progenitors during genitourinary tract development. Dev Biol 360:186-194 (2011).
109.
Wang C, Wang J, Borer JG, Li X: Embryonic origin and remodeling of the urinary and digestive outlets. PLoS One 8:e55587 (2013).
110.
Warot X, Fromental-Ramain C, Fraulob V, Chambon P, Dollé P: Gene dosage-dependent effects of the Hoxa-13 and Hoxd-13 mutations on morphogenesis of the terminal parts of the digestive and urogenital tracts. Development 124:4781-4791 (1997).
111.
White PC, Speiser PW: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 21:245-291 (2000).
112.
Wilhelm D, Koopman P: The makings of maleness: towards an integrated view of male sexual development. Nat Rev Genet 7:620-631 (2006).
113.
Wu X, Ferrara C, Shapiro E, Grishina I: Bmp7 expression and null phenotype in the urogenital system suggest a role in re-organization of the urethral epithelium. Gene Expr Patterns 9:224-230 (2009).
114.
Xu K, Wu X, Shapiro E, Huang H, Zhang L, et al: Bmp7 functions via a polarity mechanism to promote cloacal septation. PLoS One 7:e29372 (2012).
115.
Yamada G, Satoh Y, Baskin LS, Cunha GR: Cellular and molecular mechanisms of development of the external genitalia. Differentiation 71:445-460 (2003).
116.
Yao HH-C, Capel B: Disruption of testis cords by cyclopamine or forskolin reveals independent cellular pathways in testis organogenesis. Dev Biol 246:356-365 (2002).
117.
Yiou R, Delmas V, Carmeliet P, Gherardi RK, Barlovatz-Meimon G, et al: The pathophysiology of pelvic floor disorders: evidence from a histomorphologic study of the perineum and a mouse model of rectal prolapse. J Anat 199:599-607 (2001).
118.
Zhang S-W, Bai Y-Z, Zhang S-C, Wang D-J, Zhang T, et al: Embryonic development of the striated muscle complex in rats with anorectal malformations. J Pediatr Surg 43:1452-1458 (2008).
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