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.
Joseph
Nancy M
NM
Department of Internal Medicine, 1500 East Medical Center Drive, University of Michigan, Ann Arbor, MI 48109-0934, USA.
Mukouyama
Yoh-Suke
YS
Mosher
Jack T
JT
Jaegle
Martine
M
Crone
Steven A
SA
Dormand
Emma-Louise
EL
Lee
Kuo-Fen
KF
Meijer
Dies
D
Anderson
David J
DJ
Morrison
Sean J
SJ
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008954:Models, Biological; D009432:Neural Crest / Q000166:cytology* / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D011961:Receptors, Fc / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology*; D012584:Sciatic Nerve / Q000166:cytology; D013234:Stem Cells / Q000166:cytology*; D018800:Thy-1 Antigens / Q000378:metabolism
C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C037317:Fc(delta) receptor; D020890:Neuregulin-1; D011961:Receptors, Fc; D018800:Thy-1 Antigens