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Published November 15, 2004 | public
Journal Article Open

Neural crest stem cells undergo multilineage differentiation in developing peripheral nerves to generate endoneurial fibroblasts in addition to Schwann cells


Neural crest stem cells (NCSCs) persist in peripheral nerves throughout late gestation but their function is unknown. Current models of nerve development only consider the generation of Schwann cells from neural crest, but the presence of NCSCs raises the possibility of multilineage differentiation. We performed Cre-recombinase fate mapping to determine which nerve cells are neural crest derived. Endoneurial fibroblasts, in addition to myelinating and non-myelinating Schwann cells, were neural crest derived, whereas perineurial cells, pericytes and endothelial cells were not. This identified endoneurial fibroblasts as a novel neural crest derivative, and demonstrated that trunk neural crest does give rise to fibroblasts in vivo, consistent with previous studies of trunk NCSCs in culture. The multilineage differentiation of NCSCs into glial and non-glial derivatives in the developing nerve appears to be regulated by neuregulin, notch ligands, and bone morphogenic proteins, as these factors are expressed in the developing nerve, and cause nerve NCSCs to generate Schwann cells and fibroblasts, but not neurons, in culture. Nerve development is thus more complex than was previously thought, involving NCSC self-renewal, lineage commitment and multilineage differentiation.

Additional Information

Published by The Company of Biologists 2004. Open access initiative from The Company of Biologists. Accepted 3 September 2004. First published online 20 October 2004 This work was supported by the National Institutes of Health (R01 NS40750), the Searle Scholars Program, and the Howard Hughes Medical Institute. N.M.J. was supported by the MSTP, and Cell and Developmental Biology Training Grants (University of Michigan). Thanks to David Adams, Martin White, Anne Marie Deslaurier, and the University of Michigan Flow-Cytometry Core Facility. Flow-cytometry was supported in part by the UM-Comprehensive Cancer NIH CA46592, and the UM-Multipurpose Arthritis Center NIH AR20557. Thanks to Elizabeth Smith in the Hybridoma Core Facility, supported through the Michigan Diabetes Research and Training Center (P60-DK20572) and the Rheumatic Core Disease Center (1 P30 AR48310). Thanks to Chris Edwards, Dorothy Sorensen and Qian-Chun Yu for assistance with confocal and electron microscopy. Thanks to Andrew McMahon for providing Wnt1-Cre mice; to Philippe Soriano for providing loxpRosa mice; and to K. Sue O'Shea for expert advice on nerve histology. Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/131/22/5599/DC1


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