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Cholesterol Metabolism Is Required for Intracellular Hedgehog Signal Transduction


We describe the rudolph mouse, a mutant with striking defects in both central nervous system and skeletal development. Rudolph is an allele of the cholesterol biosynthetic enzyme, hydroxysteroid (17-beta) dehydrogenase 7, which is an intriguing finding given the recent implication of oxysterols in mediating intracellular Hedgehog (Hh) signaling. We see an abnormal sterol profile and decreased Hh target gene induction in the rudolph mutant, both in vivo and in vitro. Reduced Hh signaling has been proposed to contribute to the phenotypes of congenital diseases of cholesterol metabolism. Recent in vitro and pharmacological data also indicate a requirement for intracellular cholesterol synthesis for proper regulation of Hh activity via Smoothened. The data presented here are the first in vivo genetic evidence supporting both of these hypotheses, revealing a role for embryonic cholesterol metabolism in both CNS development and normal Hh signaling.


Vyšlo v časopise: Cholesterol Metabolism Is Required for Intracellular Hedgehog Signal Transduction. PLoS Genet 7(9): e32767. doi:10.1371/journal.pgen.1002224
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002224

Souhrn

We describe the rudolph mouse, a mutant with striking defects in both central nervous system and skeletal development. Rudolph is an allele of the cholesterol biosynthetic enzyme, hydroxysteroid (17-beta) dehydrogenase 7, which is an intriguing finding given the recent implication of oxysterols in mediating intracellular Hedgehog (Hh) signaling. We see an abnormal sterol profile and decreased Hh target gene induction in the rudolph mutant, both in vivo and in vitro. Reduced Hh signaling has been proposed to contribute to the phenotypes of congenital diseases of cholesterol metabolism. Recent in vitro and pharmacological data also indicate a requirement for intracellular cholesterol synthesis for proper regulation of Hh activity via Smoothened. The data presented here are the first in vivo genetic evidence supporting both of these hypotheses, revealing a role for embryonic cholesterol metabolism in both CNS development and normal Hh signaling.


Zdroje

1. FuccilloMJoynerALFishellG 2006 Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development. Nat Rev Neurosci 7 772 783

2. InghamPWMcMahonAP 2001 Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15 3059 3087

3. Wechsler-ReyaRScottMP 2001 The developmental biology of brain tumors. Annu Rev Neurosci 24 385 428

4. EggenschwilerJTAndersonKV 2007 Cilia and developmental signaling. Annu Rev Cell Dev Biol 23 345 373

5. CorbitKCAanstadPSinglaVNormanARStainierDY 2005 Vertebrate Smoothened functions at the primary cilium. Nature

6. RohatgiRMilenkovicLCorcoranRBScottMP 2009 Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci U S A 106 3196 3201

7. HuangXLitingtungYChiangC 2007 Ectopic sonic hedgehog signaling impairs telencephalic dorsal midline development: implication for human holoprosencephaly. Hum Mol Genet 16 1454 1468

8. RohatgiRMilenkovicLScottMP 2007 Patched1 regulates hedgehog signaling at the primary cilium. Science 317 372 376

9. WangYZhouZWalshCTMcMahonAP 2009 Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc Natl Acad Sci U S A 106 2623 2628

10. CooperMKPorterJAYoungKEBeachyPA 1998 Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280 1603 1607

11. CooperMKWassifCAKrakowiakPATaipaleJGongR 2003 A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet 33 508 513

12. CorcoranRBScottMP 2006 Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci U S A 103 8408 8413

13. DwyerJRSeverNCarlsonMNelsonSFBeachyPA 2007 Oxysterols are novel activators of the hedgehog signaling pathway in pluripotent mesenchymal cells. J Biol Chem 282 8959 8968

14. HermanGE 2003 Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes. Hum Mol Genet 12 Spec No 1 R75 88

15. WassifCAMaslenCKachilele-LinjewileSLinDLinckLM 1998 Mutations in the human sterol delta7-reductase gene at 11q12–13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet 63 55 62

16. MarijanovicZLaubnerDMollerGGegeCHusenB 2003 Closing the gap: identification of human 3-ketosteroid reductase, the last unknown enzyme of mammalian cholesterol biosynthesis. Mol Endocrinol 17 1715 1725

17. MoranJLBoltonADTranPVBrownADwyerND 2006 Utilization of a whole genome SNP panel for efficient genetic mapping in the mouse. Genome Res 16 436 440

18. ShehuAMaoJGiboriGBHalperinJLeJ 2008 Prolactin receptor-associated protein/17beta-hydroxysteroid dehydrogenase type 7 gene (Hsd17b7) plays a crucial role in embryonic development and fetal survival. Mol Endocrinol 22 2268 2277

19. JokelaHRantakariPLamminenTStraussLOlaR 2010 Hydroxysteroid (17beta) dehydrogenase 7 activity is essential for fetal de novo cholesterol synthesis and for neuroectodermal survival and cardiovascular differentiation in early mouse embryos. Endocrinology 151 1884 1892

20. BermanDMKarhadkarSSHallahanARPritchardJIEberhartCG 2002 Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297 1559 1561

21. WilsonCWChenMHChuangPT 2009 Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PLoS ONE 4 e5182 doi:10.1371/journal.pone.0005182

22. McLarrenKWSeversonTMdu SouichCStocktonDWKratzLE 2010 Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome. Am J Hum Genet 87 905 914

23. HeMKratzLEMichelJJVallejoANFerrisL 2011 Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay. J Clin Invest

24. PorterFDHermanGE Malformation syndromes caused by disorders of cholesterol synthesis. J Lipid Res

25. IronsMEliasERSalenGTintGSBattaAK 1993 Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet 341 1414

26. TintGSIronsMEliasERBattaAKFriedenR 1994 Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 330 107 113

27. FitzkyBUWitsch-BaumgartnerMErdelMLeeJNPaikYK 1998 Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci U S A 95 8181 8186

28. MoebiusFFFitzkyBULeeJNPaikYKGlossmannH 1998 Molecular cloning and expression of the human delta7-sterol reductase. Proc Natl Acad Sci U S A 95 1899 1902

29. WassifCAZhuPKratzLKrakowiakPABattaileKP 2001 Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith–Lemli–Opitz syndrome. Hum Mol Genet 10 555 564

30. FitzkyBUMoebiusFFAsaokaHWaage-BaudetHXuL 2001 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome. J Clin Invest 108 905 915

31. Brunetti-PierriNCorsoGRossiMFerrariPBalliF 2002 Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3beta-hydroxysteroid-delta5-desaturase. Am J Hum Genet 71 952 958

32. KrakowiakPAWassifCAKratzLCozmaDKovarovaM 2003 Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. Hum Mol Genet 12 1631 1641

33. RisleyJM 2002 Cholesterol Biosynthesis: Lanosterol to Cholesterol. Journal of Chemical Education 79 377 384

34. KonigAHappleRBornholdtDEngelHGrzeschikKH 2000 Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am J Med Genet 90 339 346

35. LiuXYDangelAWKelleyRIZhaoWDennyP 1999 The gene mutated in bare patches and striated mice encodes a novel 3beta-hydroxysteroid dehydrogenase. Nat Genet 22 182 187

36. BravermanNLinPMoebiusFFObieCMoserA 1999 Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hunermann syndrome. Nat Genet 22 291 294

37. HermanGEKelleyRIPurezaVSmithDKopaczK 2002 Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome). Genet Med 4 434 438

38. HasCSeedorfUKannenbergFBruckner-TudermanLFolkersE 2002 Gas chromatography-mass spectrometry and molecular genetic studies in families with the Conradi-Hunermann-Happle syndrome. J Invest Dermatol 118 851 858

39. WhittockNVIzattLMannAHomfrayTBennettC 2003 Novel mutations in X-linked dominant chondrodysplasia punctata (CDPX2). J Invest Dermatol 121 939 942

40. DerryJMGormallyEMeansGDZhaoWMeindlA 1999 Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. jderry@immunex.com. Nat Genet 22 286 290

41. LongFJoengKSXuanSEfstratiadisAMcMahonAP 2006 Independent regulation of skeletal growth by Ihh and IGF signaling. Dev Biol 298 327 333

42. St-JacquesBHammerschmidtMMcMahonAP 1999 Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 13 2072 2086

43. TsiairisCDMcMahonAP 2008 Disp1 regulates growth of mammalian long bones through the control of Ihh distribution. Dev Biol 317 480 485

44. WangYPDakuboGHowleyPCampsallKDMazarolleCJ 2002 Development of normal retinal organization depends on Sonic hedgehog signaling from ganglion cells. Nat Neurosci 5 831 832

45. WallaceVARaffMC 1999 A role for Sonic hedgehog in axon-to-astrocyte signalling in the rodent optic nerve. Development 126 2901 2909

46. WangYDakuboGDThurigSMazerolleCJWallaceVA 2005 Retinal ganglion cell-derived sonic hedgehog locally controls proliferation and the timing of RGC development in the embryonic mouse retina. Development 132 5103 5113

47. AhlgrenSCBronner-FraserM 1999 Inhibition of sonic hedgehog signaling in vivo results in craniofacial neural crest cell death. Curr Biol 9 1304 1314

48. FuccilloMRalluMMcMahonAPFishellG 2004 Temporal requirement for hedgehog signaling in ventral telencephalic patterning. Development 131 5031 5040

49. KomadaMSaitsuHKinboshiMMiuraTShiotaK 2008 Hedgehog signaling is involved in development of the neocortex. Development 135 2717 2727

50. LiHSWangDShenQSchonemannMDGorskiJA 2003 Inactivation of Numb and Numblike in embryonic dorsal forebrain impairs neurogenesis and disrupts cortical morphogenesis. Neuron 40 1105 1118

51. JurevicsHMorellP 1995 Cholesterol for synthesis of myelin is made locally, not imported into brain. J Neurochem 64 895 901

52. TintGSYuHShangQXuGPatelSB 2006 The use of the Dhcr7 knockout mouse to accurately determine the origin of fetal sterols. J Lipid Res 47 1535 1541

53. JurevicsHAKidwaiFZMorellP 1997 Sources of cholesterol during development of the rat fetus and fetal organs. J Lipid Res 38 723 733

54. EdmondJKorsakRAMorrowJWTorok-BothGCatlinDH 1991 Dietary cholesterol and the origin of cholesterol in the brain of developing rats. J Nutr 121 1323 1330

55. LindegaardMLWassifCAVaismanBAmarMWasmuthEV 2008 Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome. Hum Mol Genet 17 3806 3813

56. OhashiKOsugaJTozawaRKitamineTYagyuH 2003 Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene. J Biol Chem 278 42936 42941

57. HoganBBeddingtonRCostantiniFLacyE 1994 Manipulating the Mouse Embryo New York Cold Spring Harbor Press

58. MurtaughLCChyungJHLassarAB 1999 Sonic hedgehog promotes somitic chondrogenesis by altering the cellular response to BMP signaling. Genes Dev 13 225 237

59. HuiCCSlusarskiDPlattKAHolmgrenRJoynerAL 1994 Expression of three mouse homologs of the Drosophila segment polarity gene cubitus interruptus, Gli, Gli-2, and Gli-3, in ectoderm- and mesoderm-derived tissues suggests multiple roles during postimplantation development. Dev Biol 162 402 413

60. GoodrichLVJohnsonRLMilenkovicLMcMahonJAScottMP 1996 Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes and Development 10 301 312

61. KelleyRI 1995 Diagnosis of Smith-Lemli-Opitz syndrome by gas chromatography/mass spectrometry of 7-dehydrocholesterol in plasma, amniotic fluid and cultured skin fibroblasts. Clin Chim Acta 236 45 58

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