Editors' ChoiceDevelopmental Biology

Attract and Segregate

Science Signaling  26 Jun 2012:
Vol. 5, Issue 230, pp. ec176
DOI: 10.1126/scisignal.2003336

Neural crest cells are pluripotent cells that produce multiple types of cells. A population of neural crest cells that produce the sympathetic ganglion (SG) cells of the autonomic nervous system also give rise to cells of the adrenal medulla (AM), which are not part of the autonomic nervous system. The SG and AM progenitor cells are collectively referred to as SA progenitors and segregate into SG and AM populations after arriving near the dorsal aorta (the para-aortic region). Using the chick embryo, Saito et al. found that the dorsal aorta was a source of the ligands bone morphogenetic protein 4 (BMP4) and BMP7 and that these ligands promoted the appearance of phosphorylated Smad (pSmad), indicative of BMP signaling, in SA progenitors. Blocking BMP signals from the dorsal aorta with the BMP-binding protein Noggin prevented both the formation of pSmad in the SA progenitors and the accumulation of SA progenitors in the para-aortic region. However, blocking BMP signaling in the SA progenitors with a dominant-negative BMP receptor caused only mild migration defects, indicating that the BMP signal was not required for migration into the para-aortic area. pSmad was not detected in SA progenitors after they arrived in the aortic area, but it was detected later only in the AM cells. SA progenitors that had been transfected with a construct encoding a dominant-negative BMP receptor did not contribute to the AM population, suggesting that BMP signaling might play a role in specification of these cells from the SA progenitor pool. Stromal cell–derived factor 1 (SDF1) and Neuregulin 1 (NRG1) are produced in the para-aortic mesenchymal cells. Overexpression of a construct encoding Noggin in the dorsal aorta eliminated SDF1 transcripts and NRG1 protein in the para-aortic mesenchymal cells, and inhibiting SDF1 and NRG1 signaling in neural crest cells disrupted SA progenitor accumulation in the para-aortic area. Implantation of pieces of dorsal aorta into muscle tissue attracted neural crest cells to the graft site and induced SDF1 transcripts and NRG1 protein in the surrounding mesenchymal cells; implantation of SDF1- or NRG1-producing cultured mesenchymal cells into muscle tissue attracted neural crest cells to the graft. Implantation of BMP4-producing cultured mesenchymal cells did not attract neural crest cells or induce production of SDF1 or NRG1 in surrounding cells. These results suggest a model in which BMPs produced by the dorsal aorta induce production of SDF1 and NRG1 by the adjacent mesenchymal cells, which act as chemoattractants to guide the SA progenitors toward the dorsal aorta, after which BMP signaling participates in segregating the AM population from the SG population.

D. Saito, Y. Takase, H. Murai, Y. Takahashi, The dorsal aorta initiates a molecular cascade that instructs sympatho-adrenal specification. Science 336, 1578–1581 (2012). [Abstract] [Full Text]