Ancient evolutionary origin of vertebrate enteric neurons from trunk-derived neural crest

  • Nature volume 544, pages 8891 (06 April 2017)
  • doi:10.1038/nature21679
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The enteric nervous system of jawed vertebrates arises primarily from vagal neural crest cells that migrate to the foregut and subsequently colonize and innervate the entire gastrointestinal tract. Here we examine development of the enteric nervous system in the basal jawless vertebrate the sea lamprey (Petromyzon marinus) to gain insight into its evolutionary origin. Surprisingly, we find no evidence for the existence of a vagally derived enteric neural crest population in the lamprey. Rather, labelling with the lipophilic dye DiI shows that late-migrating cells, originating from the trunk neural tube and associated with nerve fibres, differentiate into neurons within the gut wall and typhlosole. We propose that these trunk-derived neural crest cells may be homologous to Schwann cell precursors, recently shown in mammalian embryos to populate post-embryonic parasympathetic ganglia1,2, including enteric ganglia3. Our results suggest that neural-crest-derived Schwann cell precursors made an important contribution to the ancient enteric nervous system of early jawless vertebrates, a role that was largely subsumed by vagal neural crest cells in early gnathostomes.

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  1. 1.

    et al. Parasympathetic ganglia derive from Schwann cell precursors. Science 345, 87–90 (2014)

  2. 2.

    et al. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors. Science 345, 82–87 (2014)

  3. 3.

    , & Neuronal differentiation in Schwann cell lineage underlies postnatal neurogenesis in the enteric nervous system. J. Neurosci. 35, 9879–9888 (2015)

  4. 4.

    in Comparative Physiology and Evolution of the Autonomic Nervous System (eds . & ) Vol. 4, Ch. 1 (Harwood Academic, 1994)

  5. 5.

    & Enteric nervous system development: migration, differentiation, and disease. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G1–G24 (2013)

  6. 6.

    & The Enteric Nervous System (Blackwell, 2006)

  7. 7.

    & The migration of neural crest cells to the wall of the digestive tract in avian embryo. J. Embryol. Exp. Morphol. 30, 31–48 (1973)

  8. 8.

    & The origin of intrinsic ganglia of trunk viscera from vagal neural crest in the chick embryo. J. Comp. Neurol. 101, 515–541 (1954)

  9. 9.

    et al. Expression of sympathetic nervous system genes in lamprey suggests their recruitment for specification of a new vertebrate feature. PLoS ONE 6, e26543 (2011)

  10. 10.

    On the development and morphology of the skeleton of the head of Petromyzon. Acta Zool. 29, 139–279 (1948)

  11. 11.

    , , , & Evidence for the existence of serotonin-, dopamine-, and noradrenaline-containing neurons in the gut of Lampetra fluviatilis. Z Zellforsch. mikrosk. Anat. 141, 33–54 (1973)

  12. 12.

    , & Immunocytochemical studies on the islet and the gut of the arctic lamprey, Lampetra japonica. Arch. Histol. Cytol. 51, 109–119 (1988)

  13. 13.

    , & An electron microscopic study of autonomic nerve cells in the cloacal region of the lamprey, Lampetra japonica. J. Neurocytol. 11, 517–532 (1982)

  14. 14.

    , & A vital dye analysis of the timing and pathways of avian trunk neural crest cell migration. Development 106, 809–816 (1989)

  15. 15.

    & Neural crest contributions to the lamprey head. Development 130, 2317–2327 (2003)

  16. 16.

    et al. Development of cephalic neural crest cells in embryos of Lampetra japonica, with special reference to the evolution of the jaw. Dev. Biol. 207, 287–308 (1999)

  17. 17.

    , & Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119, 1005–1017 (1993)

  18. 18.

    , , & The zebrafish homologue of the ret receptor and its pattern of expression during embryogenesis. Oncogene 14, 879–889 (1997)

  19. 19.

    , , & Requirement of signalling by receptor tyrosine kinase RET for the directed migration of enteric nervous system progenitor cells during mammalian embryogenesis. Development 129, 5151–5160 (2002)

  20. 20.

    , & Dual function of Slit2 in repulsion and enhanced migration of trunk, but not vagal, neural crest cells. J. Cell Biol. 162, 269–279 (2003)

  21. 21.

    et al. Immunoreactivity to glial fibrillary acid protein (GFAP) in the brain and spinal cord of the lamprey (Lampetra fluviatilis). J. Brain Res. 35, 71–78 (1993)

  22. 22.

    The structure of the peripheral nerves of the lamprey (Lampetra fluviatilis). J. Ultrastruct. Res. 4, 349–359 (1960)

  23. 23.

    The origin of the vagi and the parasympathetic ganglion cells of the viscera of the chick. Anat. Rec. 82, 185–197 (1942)

  24. 24.

    Regeneration of Müller and Mauthner axons after spinal transection in larval lampreys. J. Comp. Neurol. 168, 545–554 (1976)

  25. 25.

    Mechanisms of functional recovery and regeneration after spinal cord transection in larval sea lamprey. J. Physiol. (Lond.) 277, 395–408 (1978)

  26. 26.

    et al. Schwann cell precursors from nerve innervation are a cellular origin of melanocytes in skin. Cell 139, 366–379 (2009)

  27. 27.

    & Vagal neural crest cell migratory behavior: a transition between the cranial and trunk crest. Devel. Dyn. 240, 2084–2100 (2011)

  28. 28.

    , & Culturing lamprey embryos. Cold Spring Harb. Protoc. 2009, t5122 (2009)

  29. 29.

    , , & Ancient evolutionary origin of the neural crest gene regulatory network. Dev. Cell 13, 405–420 (2007)

  30. 30.

    , & Immunostaining of whole-mount and sectioned lamprey embryos. Cold Spring Harb. Protoc. 2009, t5126 (2009)

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We thank C. Baker, M. Piacentino, and L. Kerosuo for discussion, and M. Martik, M. Simoes-Costa, and R. Uribe for their comments on this manuscript.

Author information

Author notes

    • Stephen A. Green
    •  & Benjamin R. Uy

    These authors contributed equally to this work.


  1. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA

    • Stephen A. Green
    • , Benjamin R. Uy
    •  & Marianne E. Bronner


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The project was conceived by M.E.B., and analyses were designed by S.A.G. and M.E.B. Descriptive analyses of enteric neurons were performed by S.A.G. Cranial DiI labelling was performed by B.R.U., M.E.B., and S.A.G. Trunk DiI labelling was performed by B.R.U., S.A.G. and M.E.B. Surgeries were performed, imaged and analysed by S.A.G. and B.R.U. Schematics were drawn by S.A.G. The manuscript was written by M.E.B., S.A.G. and B.R.U.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Marianne E. Bronner.

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