1932

Abstract

The hedgehog (Hh) signaling pathway plays several diverse regulatory and patterning roles during organogenesis of the intestine and in the regulation of adult intestinal homeostasis. In the embryo, fetus, and adult, intestinal Hh signaling is paracrine: Hh ligands are expressed in the endodermally derived epithelium, while signal transduction is confined to the mesenchymal compartment, where at least a dozen distinct cell types are capable of responding to Hh signals. Epithelial Hh ligands not only regulate a variety of mesenchymal cell behaviors, but they also direct these mesenchymal cells to secrete additional soluble factors (e.g., Wnts, Bmps, inflammatory mediators) that feed back to regulate the epithelial cells themselves. Evolutionary conservation of the core Hh signaling pathway, as well as conservation of epithelial/mesenchymal cross talk in the intestine, has meant that work in many diverse model systems has contributed to our current understanding of the role of this pathway in intestinal organogenesis, which is reviewed here.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-031620-094324
2021-02-10
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/physiol/83/1/annurev-physiol-031620-094324.html?itemId=/content/journals/10.1146/annurev-physiol-031620-094324&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    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
    [Google Scholar]
  2. 2. 
    Bitgood MJ, McMahon AP. 1995. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell–cell interaction in the mouse embryo. Dev. Biol. 172:126–38
    [Google Scholar]
  3. 3. 
    Gigante ED, Caspary T. 2020. Signaling in the primary cilium through the lens of the Hedgehog pathway. Wiley Interdiscip. Rev. Dev. Biol. https://doi.org/10.1002/wdev.377
    [Crossref] [Google Scholar]
  4. 4. 
    Lee RT, Zhao Z, Ingham PW 2016. Hedgehog signalling. Development 143:367–72
    [Google Scholar]
  5. 5. 
    Wu F, Zhang Y, Sun B, McMahon AP, Wang Y 2017. Hedgehog signaling: from basic biology to cancer therapy. Cell Chem. Biol. 24:252–80
    [Google Scholar]
  6. 6. 
    Kolterud A, Grosse AS, Zacharias WJ, Walton KD, Kretovich KE et al. 2009. Paracrine Hedgehog signaling in stomach and intestine: new roles for hedgehog in gastrointestinal patterning. Gastroenterology 137:618–28
    [Google Scholar]
  7. 7. 
    Ramalho-Santos M, Melton DA, McMahon AP 2000. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127:2763–72
    [Google Scholar]
  8. 8. 
    Mao J, Kim BM, Rajurkar M, Shivdasani RA, McMahon AP 2010. Hedgehog signaling controls mesenchymal growth in the developing mammalian digestive tract. Development 137:1721–29
    [Google Scholar]
  9. 9. 
    Madison BB, Braunstein K, Kuizon E, Portman K, Qiao XT, Gumucio DL 2005. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development 132:279–89
    [Google Scholar]
  10. 10. 
    Walton KD, Kolterud A, Czerwinski MJ, Bell MJ, Prakash A et al. 2012. Hedgehog-responsive mesenchymal clusters direct patterning and emergence of intestinal villi. PNAS 109:15817–22
    [Google Scholar]
  11. 11. 
    Huangfu D, Liu A, Rakeman AS, Murcia NS, Niswander L, Anderson KV 2003. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426:83–87
    [Google Scholar]
  12. 12. 
    Rohatgi R, Milenkovic L, Scott MP 2007. Patched1 regulates hedgehog signaling at the primary cilium. Science 317:372–76
    [Google Scholar]
  13. 13. 
    Zhang XM, Ramalho-Santos M, McMahon AP 2001. Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell 106:781–92
    [Google Scholar]
  14. 14. 
    Brennan D, Chen X, Cheng L, Mahoney M, Riobo NA 2012. Noncanonical Hedgehog signaling. Vitam. Horm. 88:55–72
    [Google Scholar]
  15. 15. 
    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
    [Google Scholar]
  16. 16. 
    Zhang W, Kang JS, Cole F, Yi MJ, Krauss RS 2006. Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev. Cell 10:657–65
    [Google Scholar]
  17. 17. 
    Yao S, Lum L, Beachy P 2006. The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 125:343–57
    [Google Scholar]
  18. 18. 
    Tenzen T, Allen BL, Cole F, Kang JS, Krauss RS, McMahon AP 2006. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev. Cell 10:647–56
    [Google Scholar]
  19. 19. 
    Martinelli DC, Fan CM. 2007. Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev 21:1231–43
    [Google Scholar]
  20. 20. 
    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
    [Google Scholar]
  21. 21. 
    Biau S, Jin S, Fan CM 2013. Gastrointestinal defects of the Gas1 mutant involve dysregulated Hedgehog and Ret signaling. Biol. Open 2:144–55
    [Google Scholar]
  22. 22. 
    Liu A. 2019. Proteostasis in the Hedgehog signaling pathway. Semin. Cell Dev. Biol. 93:153–63
    [Google Scholar]
  23. 23. 
    Coquenlorge S, Yin WC, Yung T, Pan J, Zhang X et al. 2019. GLI2 Modulated by SUFU and SPOP induces intestinal stem cell niche signals in development and tumorigenesis. Cell Rep 27:3006–18.e4
    [Google Scholar]
  24. 24. 
    Wang C, Pan Y, Wang B 2010. Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors. Development 137:2001–9
    [Google Scholar]
  25. 25. 
    Roulis M, Flavell RA. 2016. Fibroblasts and myofibroblasts of the intestinal lamina propria in physiology and disease. Differentiation 92:116–31
    [Google Scholar]
  26. 26. 
    Jun JI, Lau LF. 2018. Resolution of organ fibrosis. J. Clin. Investig. 128:97–107
    [Google Scholar]
  27. 27. 
    McCarthy N, Manieri E, Storm EE, Saadatpour A, Luoma AM et al. 2020. Distinct mesenchymal cell populations generate the essential intestinal BMP signaling gradient. Cell Stem Cell 26:391–402.e5
    [Google Scholar]
  28. 28. 
    Shoshkes-Carmel M, Wang YJ, Wangensteen KJ, Toth B, Kondo A et al. 2018. Subepithelial telocytes are an important source of Wnts that supports intestinal crypts. Nature 557:242–46
    [Google Scholar]
  29. 29. 
    Kinchen J, Chen HH, Parikh K, Antanaviciute A, Jagielowicz M et al. 2018. Structural remodeling of the human colonic mesenchyme in inflammatory bowel disease. Cell 175:372–86.e17
    [Google Scholar]
  30. 30. 
    Roulis M, Kaklamanos A, Schernthanner M, Bielecki P, Zhao J et al. 2020. Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche. Nature 580:524–29
    [Google Scholar]
  31. 31. 
    Degirmenci B, Valenta T, Dimitrieva S, Hausmann G, Basler K 2018. GLI1-expressing mesenchymal cells form the essential Wnt-secreting niche for colon stem cells. Nature 558:449–53
    [Google Scholar]
  32. 32. 
    Czerwinski M, Holloway EM, Tsai YH, Wu A, Yu Q et al. 2020. In vitro and in vivo development of the human intestinal niche at single cell resolution. Cell Stem Cell In press
    [Google Scholar]
  33. 33. 
    Yazawa S, Umesono Y, Hayashi T, Tarui H, Agata K 2009. Planarian Hedgehog/Patched establishes anterior-posterior polarity by regulating Wnt signaling. PNAS 106:22329–34
    [Google Scholar]
  34. 34. 
    Rink JC, Gurley KA, Elliott SA, Sánchez Alvarado A 2009. Planarian Hh signaling regulates regeneration polarity and links Hh pathway evolution to cilia. Science 326:1406–10
    [Google Scholar]
  35. 35. 
    Tsiairis CD, McMahon AP. 2009. An Hh-dependent pathway in lateral plate mesoderm enables the generation of left/right asymmetry. Curr. Biol. 19:1912–17
    [Google Scholar]
  36. 36. 
    Nonaka S, Shiratori H, Saijoh Y, Hamada H 2002. Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418:96–99
    [Google Scholar]
  37. 37. 
    Tanaka Y, Okada Y, Hirokawa N 2005. FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination. Nature 435:172–77
    [Google Scholar]
  38. 38. 
    Meno C, Shimono A, Saijoh Y, Yashiro K, Mochida K et al. 1998. lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell 94:287–97
    [Google Scholar]
  39. 39. 
    Tsukui T, Capdevila J, Tamura K, Ruiz-Lozano P, Rodriguez-Esteban C et al. 1999. Multiple left-right asymmetry defects in Shh−/− mutant mice unveil a convergence of the Shh and retinoic acid pathways in the control of Lefty-1. . PNAS 96:11376–81
    [Google Scholar]
  40. 40. 
    Walton KD, Warner J, Hertzler PH, McClay DR 2009. Hedgehog signaling patterns mesoderm in the sea urchin. Dev. Biol. 331:26–37
    [Google Scholar]
  41. 41. 
    Hebrok M, Kim SK, St Jacques B, McMahon AP, Melton DA 2000. Regulation of pancreas development by hedgehog signaling. Development 127:4905–13
    [Google Scholar]
  42. 42. 
    Kallen B, Mastroiacovo P, Robert E 1996. Major congenital malformations in Down syndrome. Am. J. Med. Genet. 65:160–66
    [Google Scholar]
  43. 43. 
    Levy J. 1991. The gastrointestinal tract in Down syndrome. Prog. Clin. Biol. Res. 373:245–56
    [Google Scholar]
  44. 44. 
    Heanue TA, Pachnis V. 2007. Enteric nervous system development and Hirschsprung's disease: advances in genetic and stem cell studies. Nat. Rev. Neurosci. 8:466–79
    [Google Scholar]
  45. 45. 
    Uesaka T, Young HM, Pachnis V, Enomoto H 2016. Development of the intrinsic and extrinsic innervation of the gut. Dev. Biol. 417:158–67
    [Google Scholar]
  46. 46. 
    Rowitch DH, St.-Jacques B, Lee SMK, Flax JD, Snyder EY, McMahon AP. 1999. Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J. Neurosci. 19:8954–65
    [Google Scholar]
  47. 47. 
    Ngan ES, Kim KH, Hui CC 2013. Sonic hedgehog signaling and VACTERL association. Mol. Syndromol. 4:32–45
    [Google Scholar]
  48. 48. 
    Lau ST, Li Z, Lai FPL, Lui KNC, Li P et al. 2019. Activation of hedgehog signaling promotes development of mouse and human enteric neural crest cells, based on single-cell transcriptome analyses. Gastroenterology 157:1556–71.e5
    [Google Scholar]
  49. 49. 
    Yang JT, Liu CZ, Villavicencio EH, Yoon JW, Walterhouse D, Iannaccone PM 1997. Expression of human GLI in mice results in failure to thrive, early death, and patchy Hirschsprung-like gastrointestinal dilatation. Mol. Med. 3:826–35
    [Google Scholar]
  50. 50. 
    Litingtung Y, Lei L, Westphal H, Chiang C 1998. Sonic hedgehog is essential to foregut development. Nat. Genet. 20:58–61
    [Google Scholar]
  51. 51. 
    Liu JA, Lai FP, Gui HS, Sham MH, Tam PK et al. 2015. Identification of GLI mutations in patients with Hirschsprung disease that disrupt enteric nervous system development in mice. Gastroenterology 149:1837–48.e5
    [Google Scholar]
  52. 52. 
    Ngan ES, Garcia-Barcelo MM, Yip BH, Poon HC, Lau ST et al. 2011. Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans. J. Clin. Investig. 121:3467–78
    [Google Scholar]
  53. 53. 
    Fu M, Lui VCH, Sham MH, Pachnis V, Tam PKH 2004. Sonic hedgehog regulates the proliferation, differentiation, and migration of enteric neural crest cells in gut. J. Cell Biol. 166:673–84
    [Google Scholar]
  54. 54. 
    Jin S, Martinelli DC, Zheng X, Tessier-Lavigne M, Fan CM 2015. Gas1 is a receptor for sonic hedgehog to repel enteric axons. PNAS 112:E73–80
    [Google Scholar]
  55. 55. 
    McMahon AP, Ingham PW, Tabin CJ 2003. Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 53:1–114
    [Google Scholar]
  56. 56. 
    Huang H, Cotton JL, Wang Y, Rajurkar M, Zhu LJ et al. 2013. Specific requirement of Gli transcription factors in hedgehog-mediated intestinal development. J. Biol. Chem. 288:17589–96
    [Google Scholar]
  57. 57. 
    Hoch M, Pankratz MJ. 1996. Control of gut development by fork head and cell signaling molecules in Drosophila. Mech. Dev 58:3–14
    [Google Scholar]
  58. 58. 
    Kaestner KH, Silberg DG, Traber PG, Schutz G 1997. The mesenchymal winged helix transcription factor Fkh6 is required for the control of gastrointestinal proliferation and differentiation. Genes Dev 11:1583–95
    [Google Scholar]
  59. 59. 
    Ormestad M, Astorga J, Landgren H, Wang T, Johansson BR et al. 2006. Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production. Development 133:833–43
    [Google Scholar]
  60. 60. 
    Mahlapuu M, Enerback S, Carlsson P 2001. Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations. Development 128:2397–406
    [Google Scholar]
  61. 61. 
    Madison BB, McKenna LB, Dolson D, Epstein DJ, Kaestner KH 2009. FoxF1 and FoxL1 link hedgehog signaling and the control of epithelial proliferation in the developing stomach and intestine. J. Biol. Chem. 284:5936–44
    [Google Scholar]
  62. 62. 
    Kosinski C, Stange D, Xu C, Chan AS, Ho C et al. 2010. Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development. Gastroenterology 139:893–903
    [Google Scholar]
  63. 63. 
    Aoki R, Shoshkes-Carmel M, Gao N, Shin S, May CL et al. 2016. Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche. Cell. Mol. Gastroenterol. Hepatol. 2:175–88
    [Google Scholar]
  64. 64. 
    Sukegawa A, Narita T, Kameda T, Saitoh K, Nohno T et al. 2000. The concentric structure of the developing gut is regulated by Sonic hedgehog derived from endodermal epithelium. Development 127:1971–80
    [Google Scholar]
  65. 65. 
    Huycke TR, Miller BM, Gill HK, Nerurkar NL, Sprinzak D et al. 2019. Genetic and mechanical regulation of intestinal smooth muscle development. Cell 179:90–105.e21
    [Google Scholar]
  66. 66. 
    Zacharias WJ, Madison BB, Kretovich KE, Walton KD, Richards N et al. 2011. Hedgehog signaling controls homeostasis of adult intestinal smooth muscle. Dev. Biol. 355:152–62
    [Google Scholar]
  67. 67. 
    Kosinski C, Stange DE, Xu C, Chan AS, Ho C et al. 2010. Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development. Gastroenterology 139:893–903
    [Google Scholar]
  68. 68. 
    van Dop WA, Heijmans J, Buller NV, Snoek SA, Rosekrans SL et al. 2010. Loss of Indian Hedgehog activates multiple aspects of a wound healing response in the mouse intestine. Gastroenterology 139:1665–76
    [Google Scholar]
  69. 69. 
    Wang LC, Nassir F, Liu ZY, Ling L, Kuo F et al. 2002. Disruption of hedgehog signaling reveals a novel role in intestinal morphogenesis and intestinal-specific lipid metabolism in mice. Gastroenterology 122:469–82
    [Google Scholar]
  70. 70. 
    Kansu A, Ensari A, Kalayci AG, Girgin N 2000. A very rare cause of intestinal pseudoobstruction: familial visceral myopathy type IV. Acta Paediatr 89:733–36
    [Google Scholar]
  71. 71. 
    Jacobs E, Ardichvili D, Perissino A, Gottignies P, Hanssens JF 1979. A case of familial visceral myopathy with atrophy and fibrosis of the longitudinal muscle layer of the entire small bowel. Gastroenterology 77:745–50
    [Google Scholar]
  72. 72. 
    Huang H, Song TJ, Li X, Hu L, He Q et al. 2009. BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. PNAS 106:12670–75
    [Google Scholar]
  73. 73. 
    Du KL, Ip HS, Li J, Chen M, Dandre F et al. 2003. Myocardin is a critical serum response factor cofactor in the transcriptional program regulating smooth muscle cell differentiation. Mol. Cell. Biol. 23:2425–37
    [Google Scholar]
  74. 74. 
    Gurdziel K, Vogt KR, Walton KD, Schneider GK, Gumucio DL 2016. Transcriptome of the inner circular smooth muscle of the developing mouse intestine: evidence for regulation of visceral smooth muscle genes by the hedgehog target gene. cJun. Dev. Dyn. 245:614–26
    [Google Scholar]
  75. 75. 
    Kudo K, Gavin E, Das S, Amable L, Shevde LA, Reed E 2012. Inhibition of Gli1 results in altered c-Jun activation, inhibition of cisplatin-induced upregulation of ERCC1, XPD and XRCC1, and inhibition of platinum-DNA adduct repair. Oncogene 31:4718–24
    [Google Scholar]
  76. 76. 
    Ting-Berreth SA, Chuong CM. 1996. Sonic hedgehog in feather morphogenesis: induction of mesenchymal condensation and association with cell death. Dev. Dyn. 207:157–70
    [Google Scholar]
  77. 77. 
    Walton KD, Whidden M, Kolterud Å, Shoffner SK, Czerwinski MJ et al. 2016. Villification in the mouse: Bmp signals control intestinal villus patterning. Development 143:427–36
    [Google Scholar]
  78. 78. 
    Turing AM. 1952. The chemical basis of morphogenesis. Philos. Trans. R. Soc. B 237:37–72
    [Google Scholar]
  79. 79. 
    Walton KD, Mishkind D, Riddle MR, Tabin CJ, Gumucio DL 2018. Blueprint for an intestinal villus: species-specific assembly required. Wiley Interdiscip. Rev. Dev. Biol. 7:e317
    [Google Scholar]
  80. 80. 
    Shyer AE, Tallinen T, Nerurkar NL, Wei Z, Gil ES et al. 2013. Villification: how the gut gets its villi. Science 342:212–18
    [Google Scholar]
  81. 81. 
    Shyer AE, Huycke TR, Lee C, Mahadevan L, Tabin CJ 2015. Bending gradients: how the intestinal stem cell gets its home. Cell 161:569–80
    [Google Scholar]
  82. 82. 
    Freddo AM, Shoffner SK, Shao Y, Taniguchi K, Grosse AS et al. 2016. Coordination of signaling and tissue mechanics during morphogenesis of murine intestinal villi: a role for mitotic cell rounding. Integr. Biol. 8:918–28
    [Google Scholar]
  83. 83. 
    Affolter M, Caussinus E. 2008. Tracheal branching morphogenesis in Drosophila: new insights into cell behaviour and organ architecture. Development 135:2055–64
    [Google Scholar]
  84. 84. 
    Kim JE, Fei L, Yin WC, Coquenlorge S, Rao-Bhatia A et al. 2020. Single cell and genetic analyses reveal conserved populations and signaling mechanisms of gastrointestinal stromal niches. Nat. Commun. 11:334
    [Google Scholar]
  85. 85. 
    Rao-Bhatia A, Zhu M, Yin WC, Coquenlorge S, Zhang X et al. 2020. Hedgehog-activated Fat4 and PCP pathways mediate mesenchymal cell clustering and villus formation in gut development. Dev. Cell 52:647–58.e6
    [Google Scholar]
  86. 86. 
    Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC 1998. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat. Genet. 20:54–57
    [Google Scholar]
  87. 87. 
    van Dop WA, Uhmann A, Wijgerde M, Sleddens-Linkels E, Heijmans J et al. 2009. Depletion of the colonic epithelial precursor cell compartment upon conditional activation of the hedgehog pathway. Gastroenterology 136:2195–203
    [Google Scholar]
  88. 88. 
    van den Brink GR, Bleuming SA, Hardwick JCH, Schepman BL, Offerhaus GJ et al. 2004. Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. Nat. Genet. 36:277–82
    [Google Scholar]
  89. 89. 
    Zacharias WJ, Li X, Madison BB, Kretovich K, Kao JY et al. 2010. Hedgehog is an anti-inflammatory epithelial signal for the intestinal lamina propria. Gastroenterology 138:2368–77
    [Google Scholar]
  90. 90. 
    Perreault N, Katz JP, Sackett SD, Kaestner KH 2001. Foxl1 controls the Wnt/β-catenin pathway by modulating the expression of proteoglycans in the gut. J. Biol. Chem. 276:43328–33
    [Google Scholar]
  91. 91. 
    Wang CC, Biben C, Robb L, Nassir F, Barnett L et al. 2000. Homeodomain factor Nkx2-3 controls regional expression of leukocyte homing coreceptor MAdCAM-1 in specialized endothelial cells of the viscera. Dev. Biol. 224:152–67
    [Google Scholar]
  92. 92. 
    Pabst O, Zweigerdt R, Arnold HH 1999. Targeted disruption of the homeobox transcription factor Nkx2-3 in mice results in postnatal lethality and abnormal development of small intestine and spleen. Development 126:2215–25
    [Google Scholar]
  93. 93. 
    Vokes SA, Ji H, McCuine S, Tenzen T, Giles S et al. 2007. Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development 134:1977–89
    [Google Scholar]
  94. 94. 
    Lees CW, Zacharias WJ, Tremelling M, Noble CL, Nimmo ER et al. 2008. Analysis of germline GLI1 variation implicates hedgehog signalling in the regulation of intestinal inflammatory pathways. PLOS Med 5:1761–75
    [Google Scholar]
  95. 95. 
    Westendorp BF, Buller N, Karpus ON, van Dop WA, Koster J et al. 2018. Indian Hedgehog suppresses a stromal cell-driven intestinal immune response. Cell. Mol. Gastroenterol. Hepatol. 5:67–82.e1
    [Google Scholar]
  96. 96. 
    Lee JJ, Rothenberg ME, Seeley ES, Zimdahl B, Kawano S et al. 2016. Control of inflammation by stromal Hedgehog pathway activation restrains colitis. PNAS 113:E7545–53
    [Google Scholar]
  97. 97. 
    Lees C, Howie S, Sartor RB, Satsangi J 2005. The hedgehog signalling pathway in the gastrointestinal tract: implications for development, homeostasis, and disease. Gastroenterology 129:1696–710
    [Google Scholar]
  98. 98. 
    Arimura S, Matsunaga A, Kitamura T, Aoki K, Aoki M, Taketo MM 2009. Reduced level of smoothened suppresses intestinal tumorigenesis by down-regulation of Wnt signaling. Gastroenterology 137:629–38
    [Google Scholar]
  99. 99. 
    Buller NV, Rosekrans SL, Metcalfe C, Heijmans J, van Dop WA et al. 2015. Stromal Indian hedgehog signaling is required for intestinal adenoma formation in mice. Gastroenterology 148:170–80.e6
    [Google Scholar]
  100. 100. 
    Greicius G, Virshup DM. 2019. Stromal control of intestinal development and the stem cell niche. Differentiation 108:8–16
    [Google Scholar]
  101. 101. 
    Valenta T, Degirmenci B, Moor AE, Herr P, Zimmerli D et al. 2016. Wnt ligands secreted by subepithelial mesenchymal cells are essential for the survival of intestinal stem cells and gut homeostasis. Cell Rep 15:911–18
    [Google Scholar]
  102. 102. 
    van den Brink GR. 2007. Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol. Rev. 87:1343–75
    [Google Scholar]
  103. 103. 
    Bai CB, Joyner AL. 2001. Gli1 can rescue the in vivo function of Gli2. . Development 128:5161–72
    [Google Scholar]
  104. 104. 
    Nakashima H, Nakamura M, Yamaguchi H, Yamanaka N, Akiyoshi T et al. 2006. Nuclear factor-κB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. Cancer Res 66:7041–49
    [Google Scholar]
  105. 105. 
    Kasperczyk H, Baumann B, Debatin KM, Fulda S 2009. Characterization of sonic hedgehog as a novel NF-κB target gene that promotes NF-κB-mediated apoptosis resistance and tumor growth in vivo. . FASEB J 23:21–33
    [Google Scholar]
  106. 106. 
    Low JA, de Sauvage FJ 2010. Clinical experience with hedgehog pathway inhibitors. J. Clin. Oncol. 28:5321–26
    [Google Scholar]
  107. 107. 
    Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD et al. 2012. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N. Engl. J. Med. 366:2171–79
    [Google Scholar]
  108. 108. 
    Nielsen CM, Williams J, van den Brink GR, Lauwers GY, Roberts DJ 2004. Hh pathway expression in human gut tissues and in inflammatory gut diseases. Lab. Investig. 84:1631–42
    [Google Scholar]
/content/journals/10.1146/annurev-physiol-031620-094324
Loading
/content/journals/10.1146/annurev-physiol-031620-094324
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error