Advertisement

Pediatric Surgery International

, Volume 31, Issue 9, pp 787–794 | Cite as

Knockout mouse models of Hirschsprung’s disease

  • J. Zimmer
  • P. Puri
Review Article

Abstract

Purpose

Hirschsprung’s disease (HSCR) is a developmental disorder of the enteric nervous system, which occurs due to the failure of neural crest cell migration. Rodent animal models of aganglionosis have contributed greatly to our understanding of the genetic basis of HSCR. Several natural or target mutations in specific genes have been reported to produce developmental defects in neural crest migration, differentiation or survival. The aim of this study was to review the currently available knockout models of HSCR to better understand the molecular basis of HSCR.

Methods

A review of the literature using the keywords “Hirschsprung’s disease”, “aganglionosis”, “megacolon” and “knockout mice model” was performed. Resulting publications were reviewed for relevant mouse models of human aganglionosis. Reference lists were screened for additional relevant studies.

Results

16 gene knockout mouse models were identified as relevant rodent models of human HSCR. Due to the deletion of a specific gene, the phenotypes of these knockout models are diverse and range from small bowel dilatation and muscular hypertrophy to total intestinal aganglionosis.

Conclusions

Mouse models of aganglionosis have been instrumental in the discovery of the causative genes of HSCR. Although important advances have been made in understanding the genetic basis of HSCR, animal models of aganglionosis in future should further help to identify the unknown susceptibility genes in HSCR.

Keywords

Animal models Knockout mice models Hirschsprung’s disease Aganglionosis Genetics 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Ikeda K, Goto S (1984) Diagnosis and treatment of Hirschsprung’s disease in Japan. An analysis of 1628 patients. Ann Surg 199(4):400–405PubMedCentralPubMedGoogle Scholar
  2. 2.
    Puri P (2011) Hirschsprung´s disease. In: Puri P (ed) Newborn surgery, 3rd edn. Hodder Arnold, London, pp 554–565Google Scholar
  3. 3.
    Tam PKH, Garcia-Barcelo M (2009) Genetic basis of Hirschsprung’s disease. Pediatr Surg Int 25(7):543–558. doi: 10.1007/s00383-009-2402-2 PubMedGoogle Scholar
  4. 4.
    Ziegler MM, Ross AJ 3rd, Bishop HC (1987) Total intestinal aganglionosis: a new technique for prolonged survival. J Pediatr Surg 22(1):82–83PubMedGoogle Scholar
  5. 5.
    Nemeth L, Yoneda A, Kader M et al (2001) Three-dimensional morphology of gut innervation in total intestinal aganglionosis using whole-mount preparation. J Pediatr Surg 36(2):291–295. doi: 10.1053/jpsu.2001.20693 PubMedGoogle Scholar
  6. 6.
    Passarge E (1967) The genetics of Hirschsprung’s disease. Evidence for heterogeneous etiology and a study of sixty-three families. N Engl J Med 276(3):138–143. doi: 10.1056/NEJM196701192760303 PubMedGoogle Scholar
  7. 7.
    Orr JD, Scobie WG (1983) Presentation and incidence of Hirschsprung’s disease. Br Med J (Clin Res Ed) 287(6406):1671Google Scholar
  8. 8.
    Spouge D, Baird PA (1985) Hirschsprung disease in a large birth cohort. Teratology 32(2):171–177. doi: 10.1002/tera.1420320204 PubMedGoogle Scholar
  9. 9.
    Lantieri F, Griseri P, Amiel J et al (2008) The molecular genetics of Hirschsrpung´s disease. In: Holschneider AM, Puri P (eds) Hirschsprung’s disease and allied disorders, 3rd edn. Springer, Berlin, Heidelberg, pp 63–78Google Scholar
  10. 10.
    Capecchi MR (1994) Targeted gene replacement. Sci Am 270(3):52–59PubMedGoogle Scholar
  11. 11.
    Pan Z, Li J (2012) Advances in molecular genetics of Hirschsprung’s disease. Anat Rec (Hoboken) 295(10):1628–1638. doi: 10.1002/ar.22538 Google Scholar
  12. 12.
    Takahashi M, Buma Y, Iwamoto T et al (1988) Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 3(5):571–578PubMedGoogle Scholar
  13. 13.
    Schuchardt A, D’Agati V, Larsson-Blomberg L et al (1994) Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367(6461):380–383. doi: 10.1038/367380a0 PubMedGoogle Scholar
  14. 14.
    Durbec PL, Larsson-Blomberg LB, Schuchardt A et al (1996) Common origin and developmental dependence on c-ret of subsets of enteric and sympathetic neuroblasts. Development 122(1):349–358PubMedGoogle Scholar
  15. 15.
    Taraviras S, Marcos-Gutierrez CV, Durbec P et al (1999) Signalling by the RET receptor tyrosine kinase and its role in the development of the mammalian enteric nervous system. Development 126(12):2785–2797PubMedGoogle Scholar
  16. 16.
    Puri P, Shinkai T (2004) Pathogenesis of Hirschsprung’s disease and its variants: recent progress. Semin Pediatr Surg 13(1):18–24PubMedGoogle Scholar
  17. 17.
    Robertson K, Mason I (1995) Expression of ret in the chicken embryo suggests roles in regionalisation of the vagal neural tube and somites and in development of multiple neural crest and placodal lineages. Mech Dev 53(3):329–344PubMedGoogle Scholar
  18. 18.
    Pouliot Y (1992) Phylogenetic analysis of the cadherin superfamily. BioEssays 14(11):743–748. doi: 10.1002/bies.950141104 PubMedGoogle Scholar
  19. 19.
    Uesaka T, Nagashimada M, Yonemura S et al (2008) Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice. J Clin Invest 118(5):1890–1898. doi: 10.1172/JCI34425 PubMedCentralPubMedGoogle Scholar
  20. 20.
    Angrist M, Bolk S, Halushka M et al (1996) Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nat Genet 14(3):341–344. doi: 10.1038/ng1196-341 PubMedGoogle Scholar
  21. 21.
    Amiel J, Lyonnet S (2001) Hirschsprung disease, associated syndromes, and genetics: a review. J Med Genet 38(11):729–739PubMedCentralPubMedGoogle Scholar
  22. 22.
    Worley DS, Pisano JM, Choi ED et al (2000) Developmental regulation of GDNF response and receptor expression in the enteric nervous system. Development 127(20):4383–4393PubMedGoogle Scholar
  23. 23.
    Young HM, Hearn CJ, Farlie PG et al (2001) GDNF is a chemoattractant for enteric neural cells. Dev Biol 229(2):503–516. doi: 10.1006/dbio.2000.0100 PubMedGoogle Scholar
  24. 24.
    Pichel JG, Shen L, Sheng HZ et al (1996) Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382(6586):73–76. doi: 10.1038/382073a0 PubMedGoogle Scholar
  25. 25.
    Moore MW, Klein RD, Farinas I et al (1996) Renal and neuronal abnormalities in mice lacking GDNF. Nature 382(6586):76–79. doi: 10.1038/382076a0 PubMedGoogle Scholar
  26. 26.
    Sanchez MP, Silos-Santiago I, Frisen J et al (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382(6586):70–73. doi: 10.1038/382070a0 PubMedGoogle Scholar
  27. 27.
    Cacalano G, Farinas I, Wang LC et al (1998) GFRalpha1 is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron 21(1):53–62PubMedCentralPubMedGoogle Scholar
  28. 28.
    Enomoto H, Araki T, Jackman A et al (1998) GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys. Neuron 21(2):317–324PubMedGoogle Scholar
  29. 29.
    Tomac AC, Grinberg A, Huang SP et al (2000) Glial cell line-derived neurotrophic factor receptor alpha1 availability regulates glial cell line-derived neurotrophic factor signaling: evidence from mice carrying one or two mutated alleles. Neuroscience 95(4):1011–1023PubMedGoogle Scholar
  30. 30.
    Durbec P, Marcos-Gutierrez CV, Kilkenny C et al (1996) GDNF signalling through the Ret receptor tyrosine kinase. Nature 381(6585):789–793. doi: 10.1038/381789a0 PubMedGoogle Scholar
  31. 31.
    Shen L, Pichel JG, Mayeli T et al (2002) Gdnf haploinsufficiency causes Hirschsprung-like intestinal obstruction and early-onset lethality in mice. Am J Hum Genet 70(2):435–447. doi: 10.1086/338712 PubMedCentralPubMedGoogle Scholar
  32. 32.
    Gianino S, Grider JR, Cresswell J et al (2003) GDNF availability determines enteric neuron number by controlling precursor proliferation. Development 130(10):2187–2198PubMedGoogle Scholar
  33. 33.
    Roberts RR, Bornstein JC, Bergner AJ et al (2008) Disturbances of colonic motility in mouse models of Hirschsprung’s disease. Am J Physiol Gastrointest Liver Physiol 294(4):G996–G1008. doi: 10.1152/ajpgi.00558.2007 PubMedGoogle Scholar
  34. 34.
    Gariepy CE (2001) Intestinal motility disorders and development of the enteric nervous system. Pediatr Res 49(5):605–613. doi: 10.1203/00006450-200105000-00001 PubMedGoogle Scholar
  35. 35.
    Heuckeroth RO, Enomoto H, Grider JR et al (1999) Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons. Neuron 22(2):253–263PubMedGoogle Scholar
  36. 36.
    Rossi J, Luukko K, Poteryaev D et al (1999) Retarded growth and deficits in the enteric and parasympathetic nervous system in mice lacking GFR alpha2, a functional neurturin receptor. Neuron 22(2):243–252PubMedGoogle Scholar
  37. 37.
    Heuckeroth RO, Lampe PA, Johnson EM et al (1998) Neurturin and GDNF promote proliferation and survival of enteric neuron and glial progenitors in vitro. Dev Biol 200(1):116–129. doi: 10.1006/dbio.1998.8955 PubMedGoogle Scholar
  38. 38.
    Edery P, Lyonnet S, Mulligan LM et al (1994) Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature 367(6461):378–380. doi: 10.1038/367378a0 PubMedGoogle Scholar
  39. 39.
    Romeo G, Ronchetto P, Luo Y et al (1994) Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s disease. Nature 367(6461):377–378. doi: 10.1038/367377a0 PubMedGoogle Scholar
  40. 40.
    Kusafuka T, Puri P (1997) Altered RET gene mRNA expression in Hirschsprung’s disease. J Pediatr Surg 32(4):600–604PubMedGoogle Scholar
  41. 41.
    Martucciello G, Ceccherini I, Lerone M et al (2000) Pathogenesis of Hirschsprung’s disease. J Pediatr Surg 35(7):1017–1025PubMedGoogle Scholar
  42. 42.
    Paran TS, Rolle U, Puri P (2006) Enteric nervous system and developmental abnormalities in childhood. Pediatr Surg Int 22(12):945–959. doi: 10.1007/s00383-006-1782-9 PubMedGoogle Scholar
  43. 43.
    Ivanchuk SM, Myers SM, Eng C et al (1996) De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease. Hum Mol Genet 5(12):2023–2026PubMedGoogle Scholar
  44. 44.
    Martucciello G, Thompson H, Mazzola C et al (1998) GDNF deficit in Hirschsprung’s disease. J Pediatr Surg 33(1):99–102PubMedGoogle Scholar
  45. 45.
    Borrego S, Fernandez RM, Dziema H et al (2003) Investigation of germline GFRA4 mutations and evaluation of the involvement of GFRA1, GFRA2, GFRA3, and GFRA4 sequence variants in Hirschsprung disease. J Med Genet 40(3):e18PubMedCentralPubMedGoogle Scholar
  46. 46.
    Sakurai T, Yanagisawa M, Masaki T (1992) Molecular characterization of endothelin receptors. Trends Pharmacol Sci 13(3):103–108PubMedGoogle Scholar
  47. 47.
    Yanagisawa H, Yanagisawa M, Kapur RP et al (1998) Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 125(5):825–836PubMedGoogle Scholar
  48. 48.
    Baynash AG, Hosoda K, Giaid A et al (1994) Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79(7):1277–1285PubMedGoogle Scholar
  49. 49.
    Hosoda K, Hammer RE, Richardson JA et al (1994) Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79(7):1267–1276PubMedGoogle Scholar
  50. 50.
    Leibl MA, Ota T, Woodward MN et al (1999) Expression of endothelin 3 by mesenchymal cells of embryonic mouse caecum. Gut 44(2):246–252PubMedCentralPubMedGoogle Scholar
  51. 51.
    Rice J, Doggett B, Sweetser DA et al (2000) Transgenic rescue of aganglionosis and piebaldism in lethal spotted mice. Dev Dyn 217(1):120–132. doi: 10.1002/(SICI)1097-0177(200001)217:1<120:AID-DVDY11>3.0.CO;2-U PubMedGoogle Scholar
  52. 52.
    von Boyen GBT, Krammer H, Suss A et al (2002) Abnormalities of the enteric nervous system in heterozygous endothelin B receptor deficient (spotting lethal) rats resembling intestinal neuronal dysplasia. Gut 51(3):414–419Google Scholar
  53. 53.
    Zaitoun I, Erickson CS, Barlow AJ et al (2013) Altered neuronal density and neurotransmitter expression in the ganglionated region of Ednrb null mice: implications for Hirschsprung’s disease. Neurogastroenterol Motil 25(3):e233–e244. doi: 10.1111/nmo.12083 PubMedCentralPubMedGoogle Scholar
  54. 54.
    Ro S, Hwang SJ, Muto M et al (2006) Anatomic modifications in the enteric nervous system of piebald mice and physiological consequences to colonic motor activity. Am J Physiol Gastrointest Liver Physiol 290(4):G710–G718. doi: 10.1152/ajpgi.00420.2005 PubMedGoogle Scholar
  55. 55.
    Lelievre V, Favrais G, Abad C et al (2007) Gastrointestinal dysfunction in mice with a targeted mutation in the gene encoding vasoactive intestinal polypeptide: a model for the study of intestinal ileus and Hirschsprung’s disease. Peptides 28(9):1688–1699. doi: 10.1016/j.peptides.2007.05.006 PubMedCentralPubMedGoogle Scholar
  56. 56.
    Puffenberger EG, Hosoda K, Washington SS et al (1994) A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell 79(7):1257–1266PubMedGoogle Scholar
  57. 57.
    Attie T, Till M, Pelet A et al (1995) Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet 4(12):2407–2409PubMedGoogle Scholar
  58. 58.
    Auricchio A, Casari G, Staiano A et al (1996) Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. Hum Mol Genet 5(3):351–354PubMedGoogle Scholar
  59. 59.
    Kusafuka T, Wang Y, Puri P (1996) Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung’s disease. Hum Mol Genet 5(3):347–349PubMedGoogle Scholar
  60. 60.
    Amiel J, Attie T, Jan D et al (1996) Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Hum Mol Genet 5(3):355–357PubMedGoogle Scholar
  61. 61.
    Hofstra RM, Osinga J, Tan-Sindhunata G et al (1996) A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nat Genet 12(4):445–447. doi: 10.1038/ng0496-445 PubMedGoogle Scholar
  62. 62.
    Edery P, Attie T, Amiel J et al (1996) Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet 12(4):442–444. doi: 10.1038/ng0496-442 PubMedGoogle Scholar
  63. 63.
    Kusafuka T, Puri P (1997) Mutations of the endothelin-B receptor and endothelin-3 genes in Hirschsprung’s disease. Pediatr Surg Int 12(1):19–23. doi: 10.1007/BF01194795 PubMedGoogle Scholar
  64. 64.
    Kusafuka T, Wang Y, Puri P (1997) Mutation analysis of the RET, the endothelin-B receptor, and the endothelin-3 genes in sporadic cases of Hirschsprung’s disease. J Pediatr Surg 32(3):501–504PubMedGoogle Scholar
  65. 65.
    Mortell A, Montedonico S, Puri P (2006) Animal models in pediatric surgery. Pediatr Surg Int 22(2):111–128. doi: 10.1007/s00383-005-1593-4 PubMedGoogle Scholar
  66. 66.
    Pusch C, Hustert E, Pfeifer D et al (1998) The SOX10/Sox10 gene from human and mouse: sequence, expression, and transactivation by the encoded HMG domain transcription factor. Hum Genet 103(2):115–123PubMedGoogle Scholar
  67. 67.
    Kuhlbrodt K, Herbarth B, Sock E et al (1998) Sox10, a novel transcriptional modulator in glial cells. J Neurosci 18(1):237–250PubMedGoogle Scholar
  68. 68.
    Paratore C, Goerich DE, Suter U et al (2001) Survival and glial fate acquisition of neural crest cells are regulated by an interplay between the transcription factor Sox10 and extrinsic combinatorial signaling. Development 128(20):3949–3961PubMedGoogle Scholar
  69. 69.
    Kim J, Lo L, Dormand E et al (2003) SOX10 maintains multipotency and inhibits neuronal differentiation of neural crest stem cells. Neuron 38(1):17–31PubMedGoogle Scholar
  70. 70.
    Kapur RP (1999) Hirschsprung disease and other enteric dysganglionoses. Crit Rev Clin Lab Sci 36(3):225–273. doi: 10.1080/10408369991239204 PubMedGoogle Scholar
  71. 71.
    Maka M, Stolt CC, Wegner M (2005) Identification of Sox8 as a modifier gene in a mouse model of Hirschsprung disease reveals underlying molecular defect. Dev Biol 277(1):155–169. doi: 10.1016/j.ydbio.2004.09.014 PubMedGoogle Scholar
  72. 72.
    Herbarth B, Pingault V, Bondurand N et al (1998) Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease. Proc Natl Acad Sci USA 95(9):5161–5165PubMedCentralPubMedGoogle Scholar
  73. 73.
    Southard-Smith EM, Kos L, Pavan WJ (1998) Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat Genet 18(1):60–64. doi: 10.1038/ng0198-60 PubMedGoogle Scholar
  74. 74.
    Kuhlbrodt K, Schmidt C, Sock E et al (1998) Functional analysis of Sox10 mutations found in human Waardenburg-Hirschsprung patients. J Biol Chem 273(36):23033–23038PubMedGoogle Scholar
  75. 75.
    Pattyn A, Morin X, Cremer H et al (1997) Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis. Development 124(20):4065–4075PubMedGoogle Scholar
  76. 76.
    Pattyn A, Morin X, Cremer H et al (1999) The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature 399(6734):366–370. doi: 10.1038/20700 PubMedGoogle Scholar
  77. 77.
    Fan J, Tam P, Vande Woude G et al (2004) Normalization and analysis of cDNA microarrays using within-array replications applied to neuroblastoma cell response to a cytokine. Proc Natl Acad Sci USA 101(5):1135–1140. doi: 10.1073/pnas.0307557100 PubMedCentralPubMedGoogle Scholar
  78. 78.
    Trochet D, Bourdeaut F, Janoueix-Lerosey I et al (2004) Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Am J Hum Genet 74(4):761–764. doi: 10.1086/383253 PubMedCentralPubMedGoogle Scholar
  79. 79.
    Perri P, Bachetti T, Longo L et al (2005) PHOX2B mutations and genetic predisposition to neuroblastoma. Oncogene 24(18):3050–3053. doi: 10.1038/sj.onc.1208532 PubMedGoogle Scholar
  80. 80.
    Bachetti T, Matera I, Borghini S et al (2005) Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome. Hum Mol Genet 14(13):1815–1824. doi: 10.1093/hmg/ddi188 PubMedGoogle Scholar
  81. 81.
    Amiel J, Laudier B, Attie-Bitach T et al (2003) Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet 33(4):459–461. doi: 10.1038/ng1130 PubMedGoogle Scholar
  82. 82.
    Garcia-Barcelo M, Sham MH, Lui VCH et al (2003) Association study of PHOX2B as a candidate gene for Hirschsprung’s disease. Gut 52(4):563–567PubMedCentralPubMedGoogle Scholar
  83. 83.
    Fitze G, Konig IR, Paditz E et al (2008) Compound effect of PHOX2B and RET gene variants in congenital central hypoventilation syndrome combined with Hirschsprung disease. Am J Med Genet A 146A(11):1486–1489. doi: 10.1002/ajmg.a.32300 PubMedGoogle Scholar
  84. 84.
    Lai D, Schroer B (2008) Haddad syndrome: a case of an infant with central congenital hypoventilation syndrome and Hirschsprung disease. J Child Neurol 23(3):341–343. doi: 10.1177/0883073807309242 PubMedGoogle Scholar
  85. 85.
    Amiel J, Sproat-Emison E, Garcia-Barcelo M et al (2008) Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet 45(1):1–14. doi: 10.1136/jmg.2007.053959 PubMedGoogle Scholar
  86. 86.
    Goulding MD, Chalepakis G, Deutsch U et al (1991) Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. EMBO J 10(5):1135–1147PubMedCentralPubMedGoogle Scholar
  87. 87.
    Lang D, Chen F, Milewski R et al (2000) Pax3 is required for enteric ganglia formation and functions with Sox10 to modulate expression of c-ret. J Clin Invest 106(8):963–971. doi: 10.1172/JCI10828 PubMedCentralPubMedGoogle Scholar
  88. 88.
    Auerbach R (1954) Analysis of the developmental effects of a lethal mutation in the house mouse. J Exp Zool 127(2):305–329. doi: 10.1002/jez.1401270206 Google Scholar
  89. 89.
    Epstein DJ, Vekemans M, Gros P (1991) Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. Cell 67(4):767–774PubMedGoogle Scholar
  90. 90.
    Epstein DJ, Vogan KJ, Trasler DG et al (1993) A mutation within intron 3 of the Pax-3 gene produces aberrantly spliced mRNA transcripts in the splotch (Sp) mouse mutant. Proc Natl Acad Sci USA 90(2):532–536PubMedCentralPubMedGoogle Scholar
  91. 91.
    Tassabehji M, Read AP, Newton VE et al (1992) Waardenburg’s syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature 355(6361):635–636. doi: 10.1038/355635a0 PubMedGoogle Scholar
  92. 92.
    Pitera JE, Smith VV, Thorogood P et al (1999) Coordinated expression of 3′ hox genes during murine embryonal gut development: an enteric Hox code. Gastroenterology 117(6):1339–1351PubMedGoogle Scholar
  93. 93.
    Fu M, Lui Vincent Chi, Hang Sham MH et al (2004) Sonic hedgehog regulates the proliferation, differentiation, and migration of enteric neural crest cells in gut. J Cell Biol 166(5):673–684. doi: 10.1083/jcb.200401077 PubMedCentralPubMedGoogle Scholar
  94. 94.
    Rings E, van den Berg M, Stokkers P (1998) Expression of homeobox genes in the gastrointestinal tract. J Pediatr Gastroenterol Nutr 27(1):122–123PubMedGoogle Scholar
  95. 95.
    Shirasawa S, Yunker AM, Roth KA et al (1997) Enx (Hox11L1)-deficient mice develop myenteric neuronal hyperplasia and megacolon. Nat Med 3(6):646–650PubMedGoogle Scholar
  96. 96.
    Hatano M, Aoki T, Dezawa M et al (1997) A novel pathogenesis of megacolon in Ncx/Hox11L.1 deficient mice. J Clin Invest 100(4):795–801. doi: 10.1172/JCI119593 PubMedCentralPubMedGoogle Scholar
  97. 97.
    Lui Vincent C H, Cheng William W C, Leon Thomas Y Y et al (2008) Perturbation of hoxb5 signaling in vagal neural crests down-regulates ret leading to intestinal hypoganglionosis in mice. Gastroenterology 134(4):1104–1115. doi: 10.1053/j.gastro.2008.01.028 PubMedGoogle Scholar
  98. 98.
    Tennyson VM, Gershon MD, Sherman DL et al (1993) Structural abnormalities associated with congenital megacolon in transgenic mice that overexpress the Hoxa-4 gene. Dev Dyn 198(1):28–53. doi: 10.1002/aja.1001980105 PubMedGoogle Scholar
  99. 99.
    Tennyson VM, Gershon MD, Wade PR et al (1998) Fetal development of the enteric nervous system of transgenic mice that overexpress the Hoxa-4 gene. Dev Dyn 211(3):269–291. doi: 10.1002/(SICI)1097-0177(199803)211:3<269:AID-AJA8>3.0.CO;2-F PubMedGoogle Scholar
  100. 100.
    Warot X, Fromental-Ramain C, Fraulob V et al (1997) 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(23):4781–4791PubMedGoogle Scholar
  101. 101.
    Mechine-Neuville A, Lefebvre O, Bellocq J et al (2002) Increased expression of HOXA9 gene in Hirschsprung disease (Augmentation de l’expression du gene HOXA9 dans la maladie de Hirschsprung). Gastroenterol Clin Biol 26(12):1110–1117PubMedGoogle Scholar
  102. 102.
    Garcia-Barcelo MM, Miao X, Lui VCH et al (2007) Correlation between genetic variations in Hox clusters and Hirschsprung’s disease. Ann Hum Genet 71(Pt 4):526–536. doi: 10.1111/j.1469-1809.2007.00347.x PubMedGoogle Scholar
  103. 103.
    Yang JT, Liu CZ, Villavicencio EH et al (1997) Expression of human GLI in mice results in failure to thrive, early death, and patchy Hirschsprung-like gastrointestinal dilatation. Mol Med 3(12):826–835PubMedCentralPubMedGoogle Scholar
  104. 104.
    Ramalho-Santos M, Melton DA, McMahon AP (2000) Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127(12):2763–2772PubMedGoogle Scholar
  105. 105.
    Newgreen D, Young HM (2002) Enteric nervous system: development and developmental disturbances–part 2. Pediatr Dev Pathol 5(4):329–349. doi: 10.1007/s10024-002-0002-4 PubMedGoogle Scholar
  106. 106.
    Dastot-Le Moal F, Wilson M, Mowat D et al (2007) ZFHX1B mutations in patients with Mowat-Wilson syndrome. Hum Mutat 28(4):313–321. doi: 10.1002/humu.20452 PubMedGoogle Scholar
  107. 107.
    de Putte Van, Tom Francis A, Nelles L et al (2007) Neural crest-specific removal of Zfhx1b in mouse leads to a wide range of neurocristopathies reminiscent of Mowat–Wilson syndrome. Hum Mol Genet 16(12):1423–1436. doi: 10.1093/hmg/ddm093 PubMedGoogle Scholar
  108. 108.
    Wakamatsu N, Yamada Y, Yamada K et al (2001) Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat Genet 27(4):369–370. doi: 10.1038/86860 PubMedGoogle Scholar
  109. 109.
    Amiel J, Espinosa-Parrilla Y, Steffann J et al (2001) Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures. Am J Hum Genet 69(6):1370–1377. doi: 10.1086/324342 PubMedCentralPubMedGoogle Scholar
  110. 110.
    Alzahem AM, Cass DT (2008) Animal models of aganglionosis. In: Holschneider AM, Puri P (eds) Hirschsprung’s disease and allied disorders, 3rd edn. Springer, Berlin, Heidelberg, pp 51–62Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.National Children’s Research CentreOur Lady’s Children’s HospitalDublinIreland
  2. 2.School of Medicine and Medical ScienceUniversity College DublinDublinIreland
  3. 3.Conway Institute of Biomedical ResearchUniversity College DublinDublinIreland

Personalised recommendations