Advertisement

Cell and Tissue Research

, Volume 366, Issue 1, pp 13–22 | Cite as

Extrinsic innervation of ileum and pelvic flexure of foals with ileocolonic aganglionosis

  • F. Giancola
  • F. Gentilini
  • N. Romagnoli
  • A. Spadari
  • M. E. Turba
  • M. Giunta
  • J. Sadeghinezhad
  • C. Sorteni
  • R. ChiocchettiEmail author
Regular article

Abstract

Equine ileocolonic aganglionosis, which is also called lethal white foal syndrome (LWFS), is a severe congenital condition characterized by the unsuccessful colonization of neural crest progenitors in the caudal part of the small intestine and the entire large intestine. LWFS, which is attributable to a mutation in the endothelin receptor B gene, is the horse equivalent of Hirschsprung’s disease in humans. Affected foals suffer from aganglionosis or hypoganglionosis of the enteric ganglia resulting in intestinal akinesia and colic. In other species with aganglionosis, fibers of extrinsic origin show an abnormal distribution pattern within the gut wall, but we have no information to date regarding this occurrence in horses. Our present aim is to investigate the distribution of extrinsic sympathetic and sensory neural fibers in LWFS, focusing on ileum and the pelvic flexure of the colon of two LWFS foals compared with a control subject. The sympathetic fibers were immunohistochemically identified with the markers tyrosine hydroxylase and dopamine beta-hydroxylase. The extrinsic sensory fibers were identified with the markers Substance P (SP) and calcitonin gene-related peptide (CGRP). Since SP and CGRP are also synthesized by subclasses of horse intramural neurons, LWFS represents a good model for the selective study of extrinsic fiber distribution. Affected foals showed large bundles of extrinsic fibers, compared with the control, as observed in Hirschsprung’s disease. Furthermore, altered adrenergic pathways were observed, prominently in the pelvic flexure. The numbers of SP- and CGRP-immunoreactive fibers in the muscle, a target of enteric neurons, were dramatically reduced, whereas fibers deduced to be extrinsic sensory axons persisted around submucosal blood vessels. Fiber numbers in the mucosa were reduced. Thus, extrinsic innervation, contributing to modulate enteric functions, might also be affected during LWFS.

Keywords

Enteric nervous system Immunohistochemistry Hirschsprung’s disease Lethal white foal syndrome Overo coat pattern 

Notes

Acknowledgements

The excellent technical assistance of Dr. Riccardo Rinnovati is gratefully acknowledged.

Compliance with ethical standards

Funding

This research was supported by no specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

441_2016_2422_MOESM1_ESM.pdf (777 kb)
ESM 1 (PDF 776 kb)

References

  1. Baynash AG, Hosoda K, Giaid A, Richardson JA, Emoto N, Hammer RE, Yanagisawa M (1994) Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79:1277–1285CrossRefPubMedGoogle Scholar
  2. Boesmans W, Lasrado R, Vanden Berghe P, Pachnis V (2015) Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system. Glia 63:229–241CrossRefPubMedGoogle Scholar
  3. Bombardi C, Grandis A, Gardini A, Sorteni C, Clavenzani P, Chiocchetti R (2013) Expression of beta2 adrenoceptors within enteric neurons of the horse ileum. Res Vet Sci 95:837–845CrossRefPubMedGoogle Scholar
  4. Brain SD, Williams TJ (1985) Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability. Br J Pharmacol 86:855–860CrossRefPubMedPubMedCentralGoogle Scholar
  5. Brain SD, Williams TJ (1988) Substance P regulates the vasodilator activity of calcitonin gene-related peptide. Nature 335:73–75CrossRefPubMedGoogle Scholar
  6. Carnahan JF, Anderson DJ, Patterson PH (1991) Evidence that enteric neurons may derive from the sympathoadrenal lineage. Dev Biol 148:552–561CrossRefPubMedGoogle Scholar
  7. Ceccherini I, Zhang AL, Matera I, Yang G, Devoto M, Romeo G, Cass DT (1995) Interstitial deletion of the endothelin-B receptor gene in the spotting lethal (sl) rat. Hum Mol Genet 4:2089–2096CrossRefPubMedGoogle Scholar
  8. Chiocchetti R, Grandis A, Bombardi C, Lucchi ML, Dal Lago DT, Bortolami R, Furness JB (2006) Extrinsic and intrinsic sources of calcitonin gene-related peptide immunoreactivity in the lamb ileum: a morphometric and neurochemical investigation. Cell Tissue Res 323:183–196CrossRefPubMedGoogle Scholar
  9. Chiocchetti R, Bombardi C, Mongardi Fantaguzzi C, Russo D, Venturelli E, Montoneri C, Spadari A, Romagnoli N, Grandis A (2009a) Intrinsic innervation of the ileocaecal junction in the horse: preliminary study. Equine Vet J 41:759–764CrossRefPubMedGoogle Scholar
  10. Chiocchetti R, Bombardi C, Mongardi-Fantaguzzi C, Venturelli E, Russo D, Spadari A, Montoneri C, Romagnoli N, Grandis A (2009b) Intrinsic innervation of the horse ileum. Res Vet Sci 87:177–185CrossRefPubMedGoogle Scholar
  11. Chiocchetti R, Giancola F, Mazzoni M, Sorteni C, Romagnoli N, Pietra M (2015) Excitatory and inhibitory enteric innervation of horse lower esophageal sphincter. Histochem Cell Biol 143:625–635CrossRefPubMedGoogle Scholar
  12. Daniel EE, Furness JB, Costa M, Belbeck L (1987) The projections of chemically identified nerve fibres in canine ileum. Cell Tissue Res 247:377–384CrossRefPubMedGoogle Scholar
  13. Ding X, Zhao Z, Duan W, Wang S, Jin X, Xiang L (2013) Expression patterns of CXCR4 in different colon tissue segments of patients with Hirschsprung’s disease. Exp Mol Pathol 95:111–116CrossRefPubMedGoogle Scholar
  14. Facer P, Knowles CH, Tam PK, Ford AP, Dyer N, Baecker PA, Anand P (2001) Novel capsaicin (VR1) and purinergic (P2X3) receptors in Hirschsprung’s intestine. J Pediatr Surg 36:1679–1684CrossRefPubMedGoogle Scholar
  15. Finno CJ, Spier SJ, Valberg SJ (2009) Equine diseases caused by known genetic mutations. Vet J 179:336–347CrossRefPubMedGoogle Scholar
  16. Freytag C, Seeger J, Siegemund T, Grosche J, Grosche A, Freeman DE, Schusser GF, Hartig W (2008) Immunohistochemical characterization and quantitative analysis of neurons in the myenteric plexus of the equine intestine. Brain Res 1244:53–64CrossRefPubMedGoogle Scholar
  17. Gershon MD (2012) NPARM in PHOX2B: why some things just should not be expanded. J Clin Invest 122:3056–3058CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hanesch U, Schaible HG (1995) Effects of ankle joint inflammation on the proportion of calcitonin gene-related peptide (CGRP)-immunopositive perikarya in dorsal root ganglia. Prog Brain Res 104:339–347CrossRefPubMedGoogle Scholar
  19. Hartig W, Reichenbach A, Voigt C, Boltze J, Bulavina L, Schuhmann MU, Seeger J, Schusser GF, Freytag C, Grosche J (2009) Triple fluorescence labelling of neuronal, glial and vascular markers revealing pathological alterations in various animal models. J Chem Neuroanat 37:128–138CrossRefPubMedGoogle Scholar
  20. Heanue TA, Pachnis V (2006) Expression profiling the developing mammalian enteric nervous system identifies marker and candidate Hirschsprung disease genes. Proc Natl Acad Sci U S A 103:6919–6924CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hudson NP, Pearson GT, Mayhew IG (2000) Tissue culture of the enteric nervous system from equine ileum. Vet Res Commun 24:299–307CrossRefPubMedGoogle Scholar
  22. Hultgren BD (1982) Ileocolonic aganglionosis in white progeny of Overo spotted horses. J Am Vet Med Assoc 180:289–292PubMedGoogle Scholar
  23. Julian AF (1994) Ileocolonic aganglionosis in an Overo foal. N Z Vet J 42:75–76CrossRefPubMedGoogle Scholar
  24. Kapur RP (2009) Practical pathology and genetics of Hirschsprung’s disease. Semin Pediatr Surg 18:212–223CrossRefPubMedGoogle Scholar
  25. Kato H, Yamamoto T, Yamamoto H, Ohi R, So N, Iwasaki Y (1990) Immunocytochemical characterization of supporting cells in the enteric nervous system in Hirschsprung’s disease. J Pediatr Surg 25:514–519CrossRefPubMedGoogle Scholar
  26. Knowles CH, De Giorgio R, Kapur RP, Bruder E, Farrugia G, Geboes K, Gershon MD, Hutson J, Lindberg G, Martin JE, Meier-Ruge WA, Milla PJ, Smith VV, Vandervinden JM, Veress B, Wedel T (2009) Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group. Acta Neuropathol 118:271–301CrossRefPubMedGoogle Scholar
  27. Lefebvre D, Hudson NP, Elce YA, Blikslager A, Divers TJ, Handel IG, Tremaine WH, Pirie RS (2015) Clinical features and management of equine postoperative ileus (POI): Survey of Diplomates of the American Colleges of Veterinary Internal Medicine (ACVIM), Veterinary Surgeons (ACVS) and Veterinary Emergency and Critical Care (ACVECC). Equine Vet J. doi: 10.1111/evj.12520 Google Scholar
  28. Lightbody T (2002) Foal with Overo lethal white syndrome born to a registered quarter horse mare. Can Vet J 43:715–717PubMedPubMedCentralGoogle Scholar
  29. Liu JA, Lai FP, Gui HS, Sham MH, Tam PK, Garcia-Barcelo MM, Hui CC, Ngan ES (2015) Identification of GLI mutations in patients with Hirschsprung disease that disrupt enteric nervous system development in mice. Gastroenterology 149:1837-1848. doi: 10.1053/j.gastro.2015.07.060
  30. Luhken G, Fleck K, Pauciullo A, Huisinga M, Erhardt G (2012) Familiar hypopigmentation syndrome in sheep associated with homozygous deletion of the entire endothelin type-B receptor gene. PLoS One 7:e53020CrossRefPubMedPubMedCentralGoogle Scholar
  31. Matsumoto K, Hosoya T, Tashima K, Namiki T, Murayama T, Horie S (2011) Distribution of transient receptor potential vanilloid 1 channel-expressing nerve fibers in mouse rectal and colonic enteric nervous system: relationship to peptidergic and nitrergic neurons. Neuroscience 172:518–534CrossRefPubMedGoogle Scholar
  32. McCabe L, Griffin LD, Kinzer A, Chandler M, Beckwith JB, McCabe ER (1990) Overo lethal white foal syndrome: equine model of aganglionic megacolon (Hirschsprung disease). Am J Med Genet 36:336–340CrossRefPubMedGoogle Scholar
  33. McCallion AS, Chakravarti A (2001) EDNRB/EDN3 and Hirschsprung disease type II. Pigment Cell Res 14:161–169CrossRefPubMedGoogle Scholar
  34. Metallinos DL, Bowling AT, Rine J (1998) A missense mutation in the endothelin-B receptor gene is associated with lethal white foal syndrome: an equine version of Hirschsprung disease. Mamm Genome 9:426–431CrossRefPubMedGoogle Scholar
  35. Moore SW (2015) Total colonic aganglionosis and Hirschsprung’s disease: a review. Pediatr Surg Int 31:1–9CrossRefPubMedGoogle Scholar
  36. Muniz E, Lobo Ladd AA, Lobo Ladd FV, Silva AA da, Kmit FV, Borges AS, Teixeira R, Mota LS da, Belli CB, Zoppa AL de, Silva LC da, Melo MP de, Coppi AA (2013) 3-D technology used to accurately understand equine ileocolonic aganglionosis. Cells Tissues Organs 198:160–168Google Scholar
  37. Nagashimada M, Ohta H, Li C, Nakao K, Uesaka T, Brunet JF, Amiel J, Trochet D, Wakayama T, Enomoto H (2012) Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression. J Clin Invest 122:3145–3158CrossRefPubMedPubMedCentralGoogle Scholar
  38. Pavone S, Mandara MT (2010) A morphological and quantitative immunohistochemical study of the interstitial cells of Cajal in the normal equine intestinal tracts. Equine Vet J 42:358–366CrossRefPubMedGoogle Scholar
  39. Rabah R (2010) Total colonic aganglionosis: case report, practical diagnostic approach and pitfalls. Arch Pathol Lab Med 134:1467–1473PubMedGoogle Scholar
  40. Reissmann M, Ludwig A (2013) Pleiotropic effects of coat colour-associated mutations in humans, mice and other mammals. Semin Cell Dev Biol 24:576–586CrossRefPubMedGoogle Scholar
  41. Robertson K, Mason I, Hall S (1997) Hirschsprung’s disease: genetic mutations in mice and men. Gut 41:436–441CrossRefPubMedPubMedCentralGoogle Scholar
  42. Ruhl A (2005) Glial cells in the gut. Neurogastroenterol Motil 17:777–790CrossRefPubMedGoogle Scholar
  43. Russo D, Bombardi C, Grandis A, Furness JB, Spadari A, Bernardini C, Chiocchetti R (2010) Sympathetic innervation of the ileocecal junction in horses. J Comp Neurol 518:4046–4066CrossRefPubMedGoogle Scholar
  44. Russo D, Bombardi C, Castellani G, Chiocchetti R (2011) Characterization of spinal ganglion neurons in horse (Equus caballus). A morphometric, neurochemical and tracing study. Neuroscience 176:53–71CrossRefPubMedGoogle Scholar
  45. Russo D, Castellani G, Chiocchetti R (2012) Expression of high-molecular-mass neurofilament protein in horse (Equus caballus) spinal ganglion neurons. Microsc Res Tech 75:626–637CrossRefPubMedGoogle Scholar
  46. Santschi EM, Purdy AK, Valberg SJ, Vrotsos PD, Kaese H, Mickelson JR (1998) Endothelin receptor B polymorphism associated with lethal white foal syndrome in horses. Mamm Genome 9:306–309CrossRefPubMedGoogle Scholar
  47. Santschi EM, Vrotsos PD, Purdy AK, Mickelson JR (2001) Incidence of the endothelin receptor B mutation that causes lethal white foal syndrome in white-patterned horses. Am J Vet Res 62:97–103CrossRefPubMedGoogle Scholar
  48. Tomuschat C, Puri P (2015) RET gene is a major risk factor for Hirschsprung’s disease: a meta-analysis. Pediatr Surg Int 31:701–710CrossRefPubMedGoogle Scholar
  49. Uesaka T, Nagashimada M, Enomoto H (2015) Neuronal differentiation in Schwann cell lineage underlies postnatal neurogenesis in the enteric nervous system. J Neurosci 35:9879–9888CrossRefPubMedGoogle Scholar
  50. Vonderfecht SL, Bowling AT, Cohen M (1983) Congenital intestinal aganglionosis in white foals. Vet Pathol 20:65–70CrossRefPubMedGoogle Scholar
  51. Vrotsos PD, Santschi EM, Purdy AK, Mickelson JR (1999) Incidence of an endothelin receptor B mutation in white patterned horses; evidence for genetic heterogeneity in the Overo coat pattern. Plant & Animal Genomes VII Conference Proceedings, Plant & Animal Genomes VII Conference, San Diego, California, January 18-22, 1999Google Scholar
  52. Walter GC, Phillips RJ, Mcadams JL, Powley TL (2016) Individual sympathetic postganglionic neurons co-innervate myenteric ganglia and smooth muscle layers in the gastrointestinal tract of the rat. J Comp Neurol. doi: 10.1002/cne.23978 PubMedGoogle Scholar
  53. Watanabe Y, Ito T, Harada T, Kobayashi S, Ozaki T, Nimura Y (1995) Spatial distribution and pattern of extrinsic nerve strands in the aganglionic segment of congenital aganglionosis: stereoscopic analysis in spotting lethal rats. J Pediatr Surg 30:1471–1476CrossRefPubMedGoogle Scholar
  54. Watanabe Y, Ito F, Ando H, Seo T, Harada T, Kaneko K, Ishiguro Y, Kobayashi S (1998) Extrinsic nerve strands in the aganglionic segment of Hirschsprung’s disease. J Pediatr Surg 33:1233–1237CrossRefPubMedGoogle Scholar
  55. Yang GC, Croaker D, Zhang AL, Manglick P, Cartmill T, Cass D (1998) A dinucleotide mutation in the endothelin-B receptor gene is associated with lethal white foal syndrome (LWFS); a horse variant of Hirschsprung disease. Hum Mol Genet 7:1047–1052CrossRefPubMedGoogle Scholar
  56. Zuelzer WW, Wilson JL (1948) Functional intestinal obstruction on a congenital neurogenic basis in infancy. Am J Dis Child 75:40–64PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • F. Giancola
    • 1
  • F. Gentilini
    • 1
  • N. Romagnoli
    • 1
  • A. Spadari
    • 1
  • M. E. Turba
    • 1
  • M. Giunta
    • 1
  • J. Sadeghinezhad
    • 2
  • C. Sorteni
    • 1
  • R. Chiocchetti
    • 1
    Email author
  1. 1.Department of Veterinary Medical Sciences (UNI EN ISO 9001:2008)University of BolognaOzzano dell’EmiliaItaly
  2. 2.Department of Basic Sciences, Faculty of Veterinary MedicineUniversity of TehranTehranIran

Personalised recommendations