Skip to main content
SpringerLink
Log in

Ultra-structural identification of interstitial cells of Cajal in the zebrafish Danio rerio

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

The interstitial cells of Cajal (ICCs) are important mediators of gastrointestinal (GI) motility because of their role as pacemakers in the GI tract. In addition to their function, ICCs are also structurally distinct cells most easily identified by their ultra-structural features and expression of the tyrosine kinase receptor c-KIT. ICCs have been described in mammals, rodents, birds, reptiles, and amphibians, but there are no reports at the ultra-structural level of ICCs within the GI tract of an organism from the teleost lineage. We describe the presence of cells in the muscularis of the zebrafish intestine; these cells have similar features to ICCs in other vertebrates. The ICC-like cells are associated with the muscularis, are more electron-dense than surrounding smooth muscle cells, possess long cytoplasmic processes and mitochondria, and are situated opposing enteric nervous structures. In addition, immunofluorescent and immunoelectron-microscopic studies with antibodies targeting the zebrafish ortholog of a putative ICC marker, c-KIT (kita), showed c-kit immunoreactivity in zebrafish ICCs. Taken together, these data represent the first ultra-structural characterization of cells in the muscularis of the zebrafish Danio rerio and suggest that ICC differentiation in vertebrate evolution dates back to the teleost lineage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Braasch I, Salzburger W, Meyer A (2006) Asymmetric evolution in two fish-specifically duplicated receptor tyrosine kinase paralogons involved in teleost coloration. Mol Biol Evol 23:1192–1202

    Article  PubMed  CAS  Google Scholar 

  • Chen H, Redelman D, Ro S, Ward SM, Ordög T, Sanders KM (2007) Selective labeling and isolation of functional classes of interstitial cells of Cajal of human and murine small intestine. Am J Physiol Cell Physiol 292:C497–C507

    Article  PubMed  CAS  Google Scholar 

  • Davuluri G, Seiler C, Abrams J, Soriano AJ, Pack M (2010) Differential effects of thin and thick filament disruption of zebrafish smooth muscle regulatory proteins. Neurogastroenterol Motil 22:1100–e285

    Article  PubMed  CAS  Google Scholar 

  • Edling CE, Hallberg B (2007) c-Kit—a hematopoietic cell essential receptor tyrosine kinase. Int J Biochem Cell Biol 39:1995–1998

    Article  PubMed  CAS  Google Scholar 

  • Faussone-Pellegrini MS, Thuneberg L (1999) Guide to the identification of interstitial cells of Cajal. Microsc Res Tech 47:248–266

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Lopez P, Garcia-Marin V, Martínez-Murillo R, Freire M (2009) Updating old ideas and recent advances regarding the interstitial cells of Cajal. Brain Res Rev 61:154–169

    Article  PubMed  CAS  Google Scholar 

  • Hennig GW, Spencer NJ, Jokela-Willis S, Bayguinov PO, Lee HT, Ritchie LA, Ward SM, Smith TK, Sanders KM (2010) ICC-MY coordinate smooth muscle electrical and mechanical activity in the murine small intestine. Neurogastroenterol Motil 22:e138–e151

    Article  PubMed  CAS  Google Scholar 

  • Holmberg A, Olsson C, Hennig GW (2007) TTX-sensitive and TTX-insensitive control of spontaneous gut motility in the developing zebrafish (Danio rerio) larvae. J Exp Biol 210:1084–1091

    Article  PubMed  CAS  Google Scholar 

  • Horowitz B, Ward SM, Sanders KM (1999) Cellular and molecular basis for electrical rhythmicity in gastrointestinal muscles. Annu Rev Physiol 61:19–43

    Article  PubMed  CAS  Google Scholar 

  • Huizinga JD (1999) Gastrointestinal peristalsis: joint action of enteric nerves, smooth muscle, and interstitial cells of Cajal. Microsc Res Tech 47:239–247

    Article  PubMed  CAS  Google Scholar 

  • Hultman KA, Bahary N, Zon LI, Johnson SL (2007) Gene duplication of the zebrafish kit ligand and partitioning of melanocyte development functions to kit ligand a. PLoS Genet 3:e17

    Article  PubMed  Google Scholar 

  • Iino S, Horiguchi K (2006) Interstitial cells of Cajal are involved in neurotransmission in the gastrointestinal tract. Acta Histochem Cytochem 39:145–153

    Article  PubMed  CAS  Google Scholar 

  • Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM (1998) Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 152:1259–1269

    PubMed  CAS  Google Scholar 

  • Klüppel M, Huizinga JD, Malysz J, Bernstein A (1998) Developmental origin and Kit-dependent development of the interstitial cells of Cajal in the mammalian small intestine. Dev Dyn 211:60–71

    Article  PubMed  Google Scholar 

  • Komuro T (2006) Structure and organization of interstitial cells of Cajal in the gastrointestinal tract. J Physiol 576:653–658

    Article  PubMed  CAS  Google Scholar 

  • Komuro T, Seki K, Horiguchi K (1999) Ultrastructural characterization of the interstitial cells of Cajal. Arch Histol Cytol 62:295–316

    Article  PubMed  CAS  Google Scholar 

  • Krementz AB, Chapman GB (1975) Ultrastructure of the posterior half of the intestine of the channel catfish, Ictalurus punctatus. J Morphol 145:441–482

    Article  Google Scholar 

  • Matsuda M, Chitnis AB (2010) Atoh1a expression must be restricted by Notch signaling for effective morphogenesis of the posterior lateral line primordium in zebrafish. Development 137:3477–3487

    Article  PubMed  CAS  Google Scholar 

  • Mellgren EM, Johnson SL (2005) Kitb, a second zebrafish ortholog of mouse Kit. Dev Genes Evol 215:470–477

    Article  PubMed  CAS  Google Scholar 

  • Merlino G, Khanna C (2007) Fishing for the origins of cancer. Genes Dev 21:1275–1279

    Article  PubMed  CAS  Google Scholar 

  • Min KW, Leabu M (2006) Interstitial cells of Cajal (ICC) and gastrointestinal stromal tumor (GIST): facts, speculations, and myths. J Cell Mol Med 10:995–1013

    Article  PubMed  CAS  Google Scholar 

  • Miyamoto-Kikuta S, Komuro T (2007) Ultrastructural observations of the tunica muscularis in the small intestine of Xenopus laevis, with special reference to the interstitial cells of Cajal. Cell Tissue Res 328:271–279

    Article  PubMed  Google Scholar 

  • Parichy DM, Rawls JF, Pratt SJ, Whitfield TT, Johnson SL (1999) Zebrafish sparse corresponds to an orthologue of c-kit and is required for the morphogenesis of a subpopulation of melanocytes, but is not essential for hematopoiesis or primordial germ cell development. Development 126:3425–3436

    PubMed  CAS  Google Scholar 

  • Rich A, Leddon SA, Hess SL, Gibbons SJ, Miller S, Xu X, Farrugia G (2007) Kit-like immunoreactivity in the zebrafish gastrointestinal tract reveals putative ICC. Dev Dyn 236:903–911

    Article  PubMed  CAS  Google Scholar 

  • Robson ME, Glogowski E, Sommer G, Antonescu CR, Nafa K, Maki RG, Ellis N, Besmer P, Brennan M, Offit K (2004) Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res 10:1250–1254

    Article  PubMed  CAS  Google Scholar 

  • Rumessen JJ, Vanderwinden JM (2003) Interstitial cells in the musculature of the gastrointestinal tract: Cajal and beyond. Int Rev Cytol 229:115–208

    Article  PubMed  CAS  Google Scholar 

  • Vanderwinden J-M, Rumessen JJ, Bernex F, Schiffmann SN, Panthier J-J (2000) Distribution and ultrastructure of interstitial cells of Cajal in the mouse colon, using antibodies to Kit and Kit W-lacZ mice. Cell Tissue Res 302:155–170

    Article  PubMed  CAS  Google Scholar 

  • Wallace KN, Akhter S, Smith EM, Lorent K, Pack M (2005) Intestinal growth and differentiation in zebrafish. Mech Dev 122:157–173

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, Du J, Lam SH, Mathavan S, Matsudaira P, Gong Z (2010) Morphological and molecular evidence for functional organization along the rostrocaudal axis of the adult zebrafish intestine. BMC Genomics 11:392

    Article  PubMed  Google Scholar 

  • Watson HD (1981) The ultrastructure of the innervation of the intestinal wall in the teleosts Myoxocephalus scorpius and Pleuronectes platessa. Cell and Tissue Res 214:651–658

    Article  CAS  Google Scholar 

  • Wu JJ, Rothman TP, Gershon MD (2000) Development of the interstitial cell of Cajal: origin, kit dependence and neuronal and nonneuronal sources of kit ligand. J Neurosci Res 59:384–401

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, MD 20892, USA

    Evan R. Ball, Eva Szarek & Constantine A. Stratakis

  2. Laboratory of Molecular Genetics, Section on Neural Developmental Dynamics, NICHD, NIH, Bethesda, MD 20892, USA

    Miho M. Matsuda

  3. National Institute of Child Health and Human Development (NICHD), Microscopy and Imaging Core, Bethesda, MD 20892, USA

    Louis Dye

  4. Office of Research Services, Division of Veterinary Resources, National Institutes of Health, Bethesda, MD 20892, USA

    Victoria Hoffmann & Patricia M. Zerfas

  5. Department of Biological Sciences, SUNY Brockport, Brockport, NY 14420, USA

    Adam Rich

  6. Program of Differentiation, Section on Neural Developmental Dynamics, NICHD, NIH, Bethesda, MD 20892, USA

    Ajay B. Chitnis

Authors
  1. Evan R. Ball
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miho M. Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Louis Dye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Victoria Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patricia M. Zerfas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eva Szarek
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Adam Rich
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ajay B. Chitnis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Constantine A. Stratakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Constantine A. Stratakis.

Additional information

Portions of this work were generously funded by the National Institutes of Health including NIH DK071588-02; the remaining of this work was funded by the Intramural Program of NICHD, NIH.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplemental Movie 1

Three-dimensional reconstruction of the whole-mount zebrafish intestine at 7 days post-fertilization (dpf). A single kit-positive cells (green) is seen in the developing intestine, closely associated with a rich neural network of acetylated tubulin-stained cells (red). Hoechst was used as a nuclear counterstain (blue) (MOV 1442 kb)

Supplemental Movie 2

Three-dimensional reconstruction of the zebrafish intestine at 7 days post-fertilization (dpf) cut in cross section. Although few in number, kit-positive cells (green) are seen in the developing intestine near the right middle quadrant of the outermost border of the intestine, together with a rich neural network demonstrated by acetylated tubulin staining (red) and Hoechst nuclear stain (blue). Superior to the intestine, kit-positive cells are also seen in the developing nephric tubules (MOV 3228 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ball, E.R., Matsuda, M.M., Dye, L. et al. Ultra-structural identification of interstitial cells of Cajal in the zebrafish Danio rerio . Cell Tissue Res 349, 483–491 (2012). https://doi.org/10.1007/s00441-012-1434-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-012-1434-4

Keywords

Search

Navigation