Hedgehog signaling and steroidogenesis

Annual Review of Physiology

Volumn 77, Issue , 2015, Pages 105-129

  Finco, Isabella ^a   LaPensee, Christopher R ^a   Krill, Kenneth T ^a   Hammer, Gary D ^a,b,c  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF MICHIGAN COMPREHENSIVE CANCER CENTER   (United States)

^c UNIVERSITY OF MICHIGAN   (United States)

Author keywords

Adrenal; Ovary; Placenta; Sf1; Steroids; Testis

Indexed keywords

CHOLESTEROL; SONIC HEDGEHOG PROTEIN; STEROIDOGENIC FACTOR 1; STEROID;

ADRENAL GLAND; ARTICLE; CHOLESTEROL HOMEOSTASIS; CHOLESTEROL METABOLISM; CHOLESTEROL SYNTHESIS; CHOLESTEROL TRANSPORT; HUMAN; LIPID HOMEOSTASIS; METABOLIC REGULATION; NONHUMAN; OVARY; PLACENTA; PRIORITY JOURNAL; PROTEIN FAMILY; PROTEIN SECRETION; PROTEIN STRUCTURE; PROTEIN SYNTHESIS; SIGNAL TRANSDUCTION; STEROIDOGENESIS; TESTIS; ANIMAL; FEMALE; MALE; METABOLISM; PHYSIOLOGY; PREGNANCY;

ADRENAL GLANDS; ANIMALS; FEMALE; HEDGEHOG PROTEINS; HUMANS; MALE; OVARY; PLACENTA; PREGNANCY; SIGNAL TRANSDUCTION; STEROIDS; TESTIS;

EID: 84922764970     PISSN: 00664278     EISSN: 15451585     Source Type: Book Series    
DOI: 10.1146/annurev-physiol-061214-111754     Document Type: Article

References (163)

1. Nusslein-VolhardC,Wieschaus E. 1980. Mutations affecting segment number and polarity in Drosophila. Nature 287:795-801
2. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, et al. 1993. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75:1417-30
3. Krauss S, Concordet JP, Ingham PW. 1993. A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell 75:1431-44
4. Riddle RD, Johnson RL, Laufer E, Tabin C. 1993. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75:1401-16
5. Chang DT, Lopez A, von Kessler DP, Chiang C, Simandl BK, et al. 1994. Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development 120:3339-53
6. Cohen MM Jr. 2003. The hedgehog signaling network. Am. J. Med. Genet. A 123A:5-28
7. Pathi S, Pagan-Westphal S, Baker DP, Garber EA, Rayhorn P, et al. 2001. Comparative biological responses to human Sonic, Indian, and Desert hedgehog. Mech. Dev. 106:107-17
8. InghamPW,McMahonAP. 2001. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15:3059-87
9. Varjosalo M, Taipale J. 2008. Hedgehog: functions and mechanisms. Genes Dev. 22:2454-72
10. McMahon AP, Ingham PW, Tabin CJ. 2003. Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 53:1-114
11. ChiangC,LitingtungY,Lee E, YoungKE, Corden JL, et al. 1996. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383:407-13
12. Litingtung Y, Lei L,Westphal H, Chiang C. 1998. Sonic hedgehog is essential to foregut development. Nat. Genet. 20:58-61
13. Sicklick JK, Li YX, Jayaraman A,Kannangai R, Qi Y, et al. 2006. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis 27:748-57
14. Chan IS, Guy CD, Machado MV, Wank A, Kadiyala V, et al. 2014. Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis. Alcohol Clin. Exp. Res. 38(3):787-800
15. Lee JJ, Perera RM, Wang H, Wu DC, Liu XS, et al. 2014. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. PNAS 111(30):E3091-100
16. Dosch JS, Pasca diMaglianoM, Simeone DM. 2010. Pancreatic cancer and hedgehog pathway signaling: new insights. Pancreatology 10(2-3):151-57
17. Santini R, Vinci MC, Pandolfi S, Penachioni JY, Montagnani V, et al. 2012. Hedgehog-GLI signaling drives self-renewal and tumorigenicity of human melanoma-initiating cells. Stem Cells 30(9):1808-18
18. Hadden MK. 2013. Hedgehog pathway inhibitors: a patent review (2009-present). Expert Opin. Ther. Pat. 23:345-61
19. Burglin TR. 2008. The Hedgehog protein family. Genome Biol. 9:241
20. Ulloa F, Briscoe J. 2007. Morphogens and the control of cell proliferation and patterning in the spinal cord. Cell Cycle 6:2640-49
21. Guerrero I, Chiang C. 2007. A conserved mechanism of Hedgehog gradient formation by lipid modifications. Trends Cell Biol. 17:1-5
22. Zeng X, Goetz JA, Suber LM, Scott WJ Jr, Schreiner CM, Robbins DJ. 2001. A freely diffusible form of Sonic hedgehog mediates long-range signalling. Nature 411:716-20
23. Chen Y, Jiang J. 2013. Decoding the phosphorylation code in Hedgehog signal transduction. Cell Res. 23:186-200
24. Creanga A, Glenn TD, Mann RK, Saunders AM, Talbot WS, Beachy PA. 2012. Scube/You activity mediates release of dually lipid-modified Hedgehog signal in soluble form. Genes Dev. 26:1312-25
25. Yan D, Lin X. 2009. Shaping morphogen gradients by proteoglycans. Cold Spring Harb. Perspect. Biol. 1:a002493
26. Li Y, Zhang H, Litingtung Y, Chiang C. 2006. Cholesterol modification restricts the spread of Shh gradient in the limb bud. PNAS 103:6548-53
27. Lewis PM, Dunn MP,McMahon JA, LoganM,Martin JF, et al. 2001. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 105:599-612
28. BurkeR,NellenD, Bellotto M, HafenE, Senti KA, et al. 1999. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell 99:803-15
29. Porter JA, Young KE, Beachy PA. 1996. Cholesterol modification of hedgehog signaling proteins in animal development. Science 274:255-59
30. Mann RK, Beachy PA. 2004. Novel lipid modifications of secreted protein signals. Annu. Rev. Biochem. 73:891-923
31. Therond PP. 2012. Release and transportation of Hedgehog molecules. Curr. Opin. Cell Biol. 24(2):173-80
32. Allen BL, Tenzen T, McMahon AP. 2007. The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes Dev. 21:1244-57
33. Izzi L, Levesque M, Morin S, Laniel D, Wilkes BC, et al. 2011. Boc and Gas1 each form distinct Shh receptor complexeswith Ptch1 and are required for Shh-mediated cell proliferation. Dev. Cell 20:788-801
34. Allen BL, Song JY, Izzi L, Althaus IW, Kang JS, et al. 2011. Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Dev. Cell 20:775-87
35. Bai CB, Auerbach W, Lee JS, Stephen D, Joyner AL. 2002. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development 129:4753-61
36. Ahn S, Joyner AL. 2004. Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning. Cell 118:505-16
37. Yang C, Chen W, Chen Y, Jiang J. 2012. Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2. Cell Res. 22:1593-604
38. Hu J, Zhang Z, Shen WJ, Azhar S. 2010. Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutr. Metab. 7:47
39. Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL. 2004. Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain. Mol. Cell 15:259-68
40. Ikonen E. 2006. Mechanisms for cellular cholesterol transport: defects and human disease. Physiol. Rev. 86:1237-61
41. Sever N, Yang T, BrownMS, Goldstein JL, DeBose-Boyd RA. 2003. Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol. Cell 11:25-33
42. Jira PE,Waterham HR, Wanders RJ, Smeitink JA, Sengers RC, Wevers RA. 2003. Smith-Lemli-Opitz syndrome and the DHCR7 gene. Ann. Hum. Genet. 67:269-80
43. Miller WL, Bose HS. 2011. Early steps in steroidogenesis: intracellular cholesterol trafficking. J. Lipid Res. 52:2111-35
44. Horton JD, Goldstein JL, BrownMS. 2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Investig. 109:1125-31
45. Goldstein JL, DeBose-Boyd RA, BrownMS. 2006. Protein sensors formembrane sterols. Cell 124:35-46
46. BrownMS, Kovanen PT, Goldstein JL. 1979. Receptor-mediated uptake of lipoprotein-cholesterol and its utilization for steroid synthesis in the adrenal cortex. Recent Prog. Horm. Res. 35:215-57
47. Soccio RE, Breslow JL. 2003. StAR-related lipid transfer (START) proteins: mediators of intracellular lipid metabolism. J. Biol. Chem. 278:22183-86
48. Riegelhaupt JJ, Waase MP, Garbarino J, Cruz DE, Breslow JL. 2010. Targeted disruption of steroidogenic acute regulatory protein D4 leads to modest weight reduction and minor alterations in lipid metabolism. J. Lipid Res. 51:1134-43
49. MillerWL, Auchus RJ. 2011. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr. Rev. 32:81-151
50. Fardella CE, RodriguezH,Hum DW,Mellon SH, MillerWL. 1995. Artificial mutations in P450c11AS (aldosterone synthase) can increase enzymatic activity: a model for low-renin hypertension? J. Clin. Endocrinol. Metab. 80:1040-43
51. Nishimoto K, Nakagawa K, Li D, Kosaka T, Oya M, et al. 2010. Adrenocortical zonation in humans under normal and pathological conditions. J. Clin. Endocrinol. Metab. 95:2296-305
52. Mellon SH, Bair SR, Monis H. 1995. P450c11B3 mRNA, transcribed from a third P450c11 gene, is expressed in a tissue-specific, developmentally, and hormonally regulated fashion in the rodent adrenal and encodes a protein with both 11-hydroxylase and 18-hydroxylase activities. J. Biol. Chem. 270:1643-49
53. Mornet E, Dupont J, Vitek A, White PC. 1989. Characterization of two genes encoding human steroid 11 β-hydroxylase (P-45011β). J. Biol. Chem. 264:20961-67
54. Li D, Urs AN, Allegood J, Leon A, Merrill AH Jr, Sewer MB. 2007. Cyclic AMP-stimulated interaction between steroidogenic factor 1 and diacylglycerol kinase facilitates induction of CYP17. Mol. Cell. Biol. 27:6669-85
55. Sewer MB, Nguyen VQ, Huang CJ, Tucker PW, Kagawa N, Waterman MR. 2002. Transcriptional activation of human CYP17 in H295R adrenocortical cells depends on complex formation among p54nrb/NonO, protein-Associated splicing factor, and SF-1, a complex that also participates in repression of transcription. Endocrinology 143:1280-90
56. Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, et al. 2002. Aromatase-A brief overview. Annu. Rev. Physiol. 64:93-127
57. Ozisik G, Achermann JC, Meeks JJ, Jameson JL. 2003. SF1 in the development of the adrenal gland and gonads. Horm. Res. 59(Suppl. 1):94-98
58. 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 1:663-71
59. Ikeda Y, ShenWH, Ingraham HA, Parker KL. 1994. Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Mol. Endocrinol. 8:654-62
60. Morohashi K, Honda S, Inomata Y, Handa H, Omura T. 1992. A common trans-Acting factor, Ad4-binding protein, to the promoters of steroidogenic P-450s. J. Biol. Chem. 267:17913-19
61. Lala DS, Rice DA, Parker KL. 1992. Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol. Endocrinol. 6:1249-58
62. Taketo M, Parker KL, Howard TA, Tsukiyama T,Wong M, et al. 1995. Homologs of Drosophila fushitarazu factor 1 map to mouse chromosome 2 and human chromosome 9q33. Genomics 25:565-67
63. Mader S, Kumar V, de Verneuil H, Chambon P. 1989. Three amino acids of the oestrogen receptor are essential to its ability to distinguish an oestrogen from a glucocorticoid-responsive element. Nature 338:271-74
64. Umesono K, Evans RM. 1989. Determinants of target gene specificity for steroid/thyroid hormone receptors. Cell 57:1139-46
65. Val P, Lefrançois-Martinez AM, Veyssiere G, Martinez A. 2003. SF-1 a key player in the development and differentiation of steroidogenic tissues. Nucl. Recept. 1:8
66. Wilson TE, Paulsen RE, Padgett KA, Milbrandt J. 1992. Participation of non-zinc finger residues in DNA binding by two nuclear orphan receptors. Science 256:107-10
67. Wong M, Ramayya MS, Chrousos GP, Driggers PH, Parker KL. 1996. Cloning and sequence analysis of the human gene encoding steroidogenic factor1J. Mol. Endocrinol. 17:139-47
68. Ueda H, Sun GC, Murata T, Hirose S. 1992. A novel DNA-binding motif abuts the zinc finger domain of insect nuclear hormone receptor FTZ-F1 and mouse embryonal long terminal repeat-binding protein. Mol. Cell. Biol. 12:5667-72
69. Li LA, Chiang EF, Chen JC, Hsu NC, Chen YJ, Chung BC. 1999. Function of steroidogenic factor 1 domains in nuclear localization, transactivation, and interaction with transcription factor TFIIB and c-Jun. Mol. Endocrinol. 13:1588-98
70. Achermann JC, Ozisik G, ItoM,Orun UA, Harmanci K, et al. 2002. Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J. Clin. Endocrinol. Metab. 87:1829-33
71. Sekido R, Lovell-Badge R. 2008. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 453:930-34
72. Wang CY, ChenWY, Lai PY, Chung BC. 2013. Distinct functions of steroidogenic factor-1 (NR5A1) in the nucleus and the centrosome. Mol. Cell. Endocrinol. 371:148-53
73. Schimmer BP, White PC. 2010. Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol. Endocrinol. 24:1322-37
74. Moore CC, Miller WL. 1991. The role of transcriptional regulation in steroid hormone biosynthesis. J. Steroid Biochem. Mol. Biol. 40:517-25
75. Payne AH, Youngblood GL. 1995. Regulation of expression of steroidogenic enzymes in Leydig cells. Biol. Reprod. 52:217-25
76. Hammer GD, Krylova I, Zhang Y, Darimont BD, Simpson K, et al. 1999. Phosphorylation of the nuclear receptor SF-1 modulates cofactor recruitment: integration of hormone signaling in reproduction and stress. Mol. Cell 3:521-26
77. Lewis AE, Rusten M, Hoivik EA, Vikse EL, HanssonML, et al. 2008. Phosphorylation of steroidogenic factor 1 is mediated by cyclin-dependent kinas7. Mol. Endocrinol. 22:91-104
78. Chen WY, Juan LJ, Chung BC. 2005. SF-1 (nuclear receptor 5A1) activity is activated by cyclic AMP via p300-mediated recruitment to active foci, acetylation, and increased DNA binding. Mol. Cell. Biol. 25:10442-53
79. Chen WY, Weng JH, Huang CC, Chung BC. 2007. Histone deacetylase inhibitors reduce steroidogenesis through SCF-mediated ubiquitination and degradation of steroidogenic factor 1 (NR5A1). Mol. Cell. Biol. 27:7284-90
80. Chen WY, Lee WC, Hsu NC, Huang F, Chung BC. 2004. SUMO modification of repression domains modulates function of nuclear receptor 5A1 (steroidogenic factor-1). J. Biol. Chem. 279(37):38730-35
81. Komatsu T, Mizusaki H, Mukai T, Ogawa H, Baba D, et al. 2004. Small ubiquitin-like modifier 1 (SUMO-1) modification of the synergy control motif of Ad4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1) regulates synergistic transcription between Ad4BP/SF-1 and Sox9. Mol. Endocrinol. 18(10):2451-62
82. LeeMB, Lebedeva LA, SuzawaM,Wadekar SA, DesclozeauxM, Ingraham HA. 2005. The DEAD-box protein DP103 (Ddx20 or Gemin-3) represses orphan nuclear receptor activity via SUMO modification. Mol. Cell. Biol. 25(5):1879-90
83. Campbell LA, Faivre EJ, Show MD, Ingraham JG, Flinders J, et al. 2008. Decreased recognition of SUMO-sensitive target genes following modification of SF-1 (NR5A1). Mol. Cell. Biol. 28:7476-86
84. Yang WH, Heaton JH, Brevig H, Mukherjee S, Iniguez-Lluhi JA, Hammer GD. 2009. SUMOylation inhibits SF-1 activity by reducingCDK7-mediated serine 203 phosphorylation. Mol. Cell. Biol. 29:613-25
85. Ikeda Y, Swain A, Weber TJ, Hentges KE, Zanaria E, et al. 1996. Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: potential links in endocrine development. Mol. Endocrinol. 10:1261-72
86. Babu PS, Bavers DL, Beuschlein F, Shah S, Jeffs B, et al. 2002. Interaction between Dax-1 and steroidogenic factor-1 in vivo: increased adrenal responsiveness to ACTH in the absence of Dax-1. Endocrinology 143:665-73
87. Lalli E, Melner MH, Stocco DM, Sassone-Corsi P. 1998. DAX-1 blocks steroid production at multiple levels. Endocrinology 139:4237-43
88. Luo X, Ikeda Y, Parker KL. 1994. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77:481-90
89. Bland ML, Jamieson CA, Akana SF, Bornstein SR, Eisenhofer G, et al. 2000. Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response. PNAS 97:14488-93
90. Zubair M, Oka S, Parker KL, Morohashi K. 2009. Transgenic expression of Ad4BP/SF-1 in fetal adrenal progenitor cells leads to ectopic adrenal formation. Mol. Endocrinol. 23:1657-67
91. Doghman M, Karpova T, Rodrigues GA, Arhatte M, De Moura J, et al. 2007. Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol. Endocrinol. 21:2968-87
92. Bashamboo A, McElreavey K. 2013. Gene mutations associated with anomalies of human gonad formation. Sex. Dev. 7:126-46
93. R opke A, Tewes AC, Gromoll J, Kliesch S,Wieacker P, Tuttelmann F. 2013. Comprehensive sequence analysis of the NR5A1 gene encoding steroidogenic factor 1 in a large group of infertile males. Eur. J. Hum. Genet. 21:1012-15
94. K ohler B, Achermann JC. 2010. Update-steroidogenic factor 1 (SF-1, NR5A1). Minerva Endocrinol. 35(2):73-86
95. Lourenco D, Brauner R, Lin L, De Perdigo A,Weryha G, et al. 2009. Mutations in NR5A1 associated with ovarian insufficiency. N. Engl. J. Med. 360:1200-10
96. Philibert P, Paris F, Lakhal B, Audran F, Gaspari L, et al. 2012. NR5A1 (SF-1) gene variants in a group of 26 young women with XX primary ovarian insufficiency. Fertil. Steril. 99(2):484-89
97. Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL. 1999. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat. Genet. 22:125-26
98. Malikova J, Camats N, Fernández-Cancio M, Heath K, González I, et al. 2014. Human NR5A1/SF-1 mutations show decreased activity on BDNF (brain-derived neurotrophic factor), an important regulator of energy balance: testing impact of novel SF-1 mutations beyond steroidogenesis. PLOS ONE 9(8):e104838
99. Buaas FW, Gardiner JR, Clayton S, Val P, Swain A. 2012. In vivo evidence for the crucial role of SF1 in steroid-producing cells of the testis, ovary and adrenal gland. Development 139:4561-70
100. Zubair M, Parker KL, Morohashi K. 2008. Developmental links between the fetal and adult zones of the adrenal cortex revealed by lineage tracing. Mol. Cell. Biol. 28:7030-40
101. Zubair M, Ishihara S, Oka S, Okumura K, Morohashi K. 2006. Two-step regulation of Ad4BP/SF-1 gene transcription during fetal adrenal development: initiation by a Hox-Pbx1-Prep1 complex and maintenance via autoregulation by Ad4BP/SF-1. Mol. Cell. Biol. 26:4111-21
102. Wood MA, Hammer GD. 2011. Adrenocortical stem and progenitor cells: unifying model of two proposed origins. Mol. Cell. Endocrinol. 336:206-12
103. Mitani F, Suzuki H, Hata J, Ogishima T, Shimada H, Ishimura Y. 1994. A novel cell layer without corticosteroid-synthesizing enzymes in rat adrenal cortex: histochemical detection and possible physiological role. Endocrinology 135:431-38
104. Mitani F, Mukai K, Miyamoto H, Suematsu M, Ishimura Y. 2003. The undifferentiated cell zone is a stem cell zone in adult rat adrenal cortex. Biochim. Biophys. Acta 1619:317-24
105. Huang CC, Miyagawa S, MatsumaruD, Parker KL, YaoHH. 2010. Progenitor cell expansion and organ size of mouse adrenal is regulated by sonic hedgehog. Endocrinology 151:1119-28
106. Ching S, Vilain E. 2009. Targeted disruption of Sonic Hedgehog in the mouse adrenal leads to adrenocortical hypoplasia. Genesis 47:628-37
107. King P, Paul A, Laufer E. 2009. Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. PNAS 106:21185-90
108. Guasti L, Paul A, Laufer E, King P. 2011. Localization of Sonic hedgehog secreting and receiving cells in the developing and adult rat adrenal cortex. Mol. Cell. Endocrinol. 336:117-22
109. Paul A, Laufer E. 2011. Endogenous biotin as a marker of adrenocortical cells with steroidogenic potential. Mol. Cell. Endocrinol. 336:133-40
110. Laufer E, Kesper D, Vortkamp A, King P. 2012. Sonic hedgehog signaling during adrenal development. Mol. Cell. Endocrinol. 351:19-27
111. Werminghaus P, Haase M, Hornsby PJ, Schinner S, Schott M, et al. 2014. Hedgehog-signaling is upregulated in non-producing human adrenal adenomas and antagonism of hedgehog-signaling inhibits proliferation of NCI-H295R cells and an immortalized primary human adrenal cell line. J. Steroid Biochem. Mol. Biol. 139:7-15
112. Wood MA, Acharya A, Finco I, Swonger JM, ElstonMJ, et al. 2013. Fetal adrenal capsular cells serve as progenitor cells for steroidogenic and stromal adrenocortical cell lineages in M. musculus. Development 140:4522-32
113. Walczak EM,Kuick R, Finco I,Bohin N, Hrycaj SM, et al. 2014. Wnt-signaling inhibits adrenal steroidogenesis by cell-Autonomous and non-cell-Autonomous mechanisms. Mol. Endocrinol. 28(9):1471-86
114. Lee FY, Faivre EJ, SuzawaM, Lontok E, Ebert D, et al. 2011. Eliminating SF-1 (NR5A1) sumoylation in vivo results in ectopic hedgehog signaling and disruption of endocrine development. Dev. Cell 21:315-27
115. Guasti L, Cavlan D, Cogger K, Banu Z, Shakur A, et al. 2013. Dlk1 up-regulates Gli1 expression in male rat adrenal capsule cells through the activation of β1 integrin and ERK1/2. Endocrinology 154:4675-84
116. Freedman BD, Kempna PB,Carlone DL, ShahMS, Guagliardo NA, et al. 2013. Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Dev. Cell 26:666-73
117. Gondos B, Rao A, Ramachandran J. 1980. Effects of antiserum to luteinizing hormone on the structure and function of rat Leydig cells. J. Endocrinol. 87:265-70
118. Bitgood MJ, Shen L, McMahon AP. 1996. Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr. Biol. 6:298-304
119. Huang CC, Yao HH. 2010. Diverse functions of Hedgehog signaling in formation and physiology of steroidogenic organs. Mol. Reprod. Dev. 77:489-96
120. Clark AM, Garland KK, Russell LD. 2000. 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. 63:1825-38
121. Barsoum I, Yao HH. 2011. Redundant and differential roles of transcription factors Gli1 and Gli2 in the development of mouse fetal Leydig cells. Biol. Reprod. 84:894-99
122. Szczepny A, Hime GR, Loveland KL. 2006. Expression of hedgehog signalling components in adult mouse testis. Dev. Dyn. 235:3063-70
123. Yao HH, Capel B. 2002. Disruption of testis cords by cyclopamine or forskolin reveals independent cellular pathways in testis organogenesis. Dev. Biol. 246:356-65
124. Umehara F, Tate G, Itoh K, Yamaguchi N, Douchi T, et al. 2000. A novel mutation of desert hedgehog in a patient with 46,XY partial gonadal dysgenesis accompanied by minifascicular neuropathy. Am. J. Hum. Genet. 67:1302-5
125. Umehara F, Mishima K, Egashira N, Ogata A, Iwasaki K, Fujiwara M. 2006. Elevated anxiety-like and depressive behavior in Desert hedgehog knockout male mice. Behav. Brain Res. 174:167-73
126. Jameson JL. 2004. Of mice and men: the tale of steroidogenic factor-1. J. Clin. Endocrinol. Metab. 89:5927-29
127. Mallet D, Bretones P, Michel-Calemard L, Dijoud F, David M, Morel Y. 2004. Gonadal dysgenesis without adrenal insufficiency in a 46,XY patient heterozygous for the nonsense C16X mutation: a case of SF1 haploinsufficiency. J. Clin. Endocrinol. Metab. 89:4829-32
128. Park SY, Meeks JJ, Raverot G, Pfaff LE, Weiss J, et al. 2005. Nuclear receptors Sf1 and Dax1 function cooperatively tomediate somatic cell differentiation during testis development. Development 132:2415-23
129. Barsoum IB, Bingham NC, Parker KL, Jorgensen JS, Yao HH. 2009. Activation of the Hedgehog pathway in the mouse fetal ovary leads to ectopic appearance of fetal Leydig cells and female pseudohermaphroditism. Dev. Biol. 329:96-103
130. Forbes AJ, Spradling AC, Ingham PW, Lin H. 1996. The role of segment polarity genes during early oogenesis in Drosophila. Development 122:3283-94
131. Zhang Y, Kalderon D. 2000. Regulation of cell proliferation and patterning in Drosophila oogenesis by Hedgehog signaling. Development 127:2165-76
132. O'Hara WA, Azar WJ, Behringer RR, RenfreeMB, Pask AJ. 2011. Desert hedgehog is a mammal-specific gene expressed during testicular and ovarian development in a marsupial. BMC Dev. Biol. 11:72
133. Ren Y, Cowan RG, Harman RM, Quirk SM. 2009. Dominant activation of the hedgehog signaling pathway in the ovary alters theca development and prevents ovulation. Mol. Endocrinol. 23:711-23
134. Ren Y, Cowan RG, Migone FF, Quirk SM. 2012. Overactivation of hedgehog signaling alters development of the ovarian vasculature in mice. Biol. Reprod. 86:174
135. Russell MC, Cowan RG, Harman RM, Walker AL, Quirk SM. 2007. The hedgehog signaling pathway in the mouse ovary. Biol. Reprod. 77:226-36
136. Wijgerde M, Ooms M, Hoogerbrugge JW, Grootegoed JA. 2005. Hedgehog signaling in mouse ovary: Indian hedgehog and desert hedgehog from granulosa cells induce target gene expression in developing theca cells. Endocrinology 146:3558-66
137. Young JM, McNeilly AS. 2010. Theca: the forgotten cell of the ovarian follicle. Reproduction 140:489-504
138. Spicer LJ, Sudo S, Aad PY, Wang LS, Chun SY, et al. 2009. 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 138:329-39
139. Sugawara T, Holt JA, Driscoll D, Strauss JF 3rd,Lin D, et al. 1995.Humansteroidogenic acute regulatory protein: functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome13. PNAS 92:4778-82
140. Sadovsky Y, Crawford PA, Woodson KG, Polish JA, Clements MA, et al. 1995. Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chaincleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. PNAS 92:10939-43
141. Ben-Zimra M, Koler M, Orly J. 2002. Transcription of cholesterol side-chain cleavage cytochrome P450 in the placenta: Activating protein-2 assumes the role of steroidogenic factor-1 by binding to an overlapping promoter element. Mol. Endocrinol. 16:1864-80
142. Huang N, Miller WL. 2000. Cloning of factors related to HIV-inducible LBP proteins that regulate steroidogenic factor-1-independent human placental transcription of the cholesterol side-chain cleavage enzyme, P450scc. J. Biol. Chem. 275:2852-58
143. MatsumotoH,ZhaoX,Das SK,HoganBL, Dey SK. 2002. Indian hedgehog as a progesterone-responsive factor mediating epithelial-mesenchymal interactions in the mouse uterus. Dev. Biol. 245:280-90
144. Takamoto N, Zhao B, Tsai SY, DeMayo FJ. 2002. Identification of Indian hedgehog as a progesteroneresponsive gene in the murine uterus. Mol. Endocrinol. 16:2338-48
145. Lee K, Jeong J, Kwak I, Yu CT, Lanske B, et al. 2006. Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nat. Genet. 38:1204-9
146. Franco HL, Lee KY, Rubel CA, Creighton CJ, White LD, et al. 2010. Constitutive activation of smoothened leads to female infertility and altered uterine differentiation in the mouse. Biol. Reprod. 82:991-99
147. Kelley RL, Roessler E, Hennekam RC, Feldman GL, Kosaki K, et al. 1996. Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: Does abnormal cholesterolmetabolism affect the function of Sonic Hedgehog? Am. J. Med. Genet. 66:478-84
148. Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, et al. 1996. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat. Genet. 14:357-60
149. CooperMK, WassifCA, Krakowiak PA,Taipale J, Gong R, et al. 2003.Adefective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat. Genet. 33:508-13
150. Koide T, Hayata T, Cho KW. 2006. Negative regulation of Hedgehog signaling by the cholesterogenic enzyme 7-dehydrocholesterol reductase. Development 133:2395-405
151. Porter FD, Herman GE. 2011. Malformation syndromes caused by disorders of cholesterol synthesis. J. Lipid Res. 52:6-34
152. Bijlsma MF, Spek CA, Zivkovic D, van deWater S, Rezaee F, Peppelenbosch MP. 2006. Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLOS Biol. 4:e232
153. Kang S, Graham JM Jr, Olney AH, Biesecker LG. 1997. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat. Genet. 15:266-68
154. Karpac J, Ostwald D, Bui S, Hunnewell P, Shankar M, Hochgeschwender U. 2005. Development, maintenance, and function of the adrenal gland in early postnatal proopiomelanocortin-null mutant mice. Endocrinology 146:2555-62
155. B ose J,Grotewold L, Ruther U. 2002. Pallister-Hall syndrome phenotype inmice mutant for Gli3. Hum. Mol. Genet. 11:1129-35
156. Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK. 2005. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLOS Genet. 1:e53
157. Szkandera J,Kiesslich T, Haybaeck J, Gerger A, PichlerM. 2013. Hedgehog signaling pathway in ovarian cancer. Int. J. Mol. Sci. 14:1179-96
158. Giordano TJ,Thomas DG, Kuick R, Lizyness M, MisekDE, et al. 2003. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am. J. Pathol. 162:521-31
159. Giordano TJ, Kuick R, Else T, Gauger PG, Vinco M, et al. 2009. Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin. Cancer Res. 15:668-76
160. Ragazzon B, Libe R, Gaujoux S, Assie G, Fratticci A, et al. 2010. Transcriptome analysis reveals that p53 and β-catenin alterations occur in a group of aggressive adrenocortical cancers. Cancer Res. 70:8276-81
161. AssieG, Letouze E, FassnachtM, Jouinot A, Luscap W, et al. 2014. Integrated genomic characterization of adrenocortical carcinoma. Nat. Genet. 46:607-12
162. Liao X, Siu MK, Au CW, Wong ES, Chan HY, et al. 2009. Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation. Carcinogenesis 30:131-40
163. Kaye SB, Fehrenbacher L, Holloway R, Amit A, Karlan B, et al. 2012. A phase II, randomized, placebocontrolled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission. Clin. Cancer Res. 18:6509-18.