Editors' ChoiceDevelopment

Innervation for Branching

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Sci. Signal.  28 Sep 2010:
Vol. 3, Issue 141, pp. ec301
DOI: 10.1126/scisignal.3141ec301

Innervation by the peripheral nervous system has been implicated in the development of several organs that form by branching morphogenesis, including mammary and prostate glands, but the precise nature of the interaction between neurons and branching epithelia is not clear. Knox et al. report that innervation by the cholinergic parasympathetic submandibular ganglion (PSG) is required for maintenance of epithelial progenitor cells in the mouse embryonic submandibular gland (SMG). Denervated SMG explants produced fewer branches than did intact explants and exhibited reduced expression of epithelial progenitor cell markers. The branching defect was phenocopied by treating intact SMG explants with any one of several agents that interfere with acetylcholine (ACh) signaling: an irreversible muscarinic (M) receptor inhibitor, the competitive muscarinic antagonist atropine, a drug that depletes ACh stores, or a small interfering RNA targeting the M1 receptor. Because ACh signaling through M1 induces the release of heparin-binding epidermal growth factor (HBEGF) in prostate epithelia, the authors tested the effect of HBEGF on SMG explants. Isolated SMG epithelia cultured with HBEGF, with the ACh analog carbachol (CCh), or with HBEGF plus CCh showed increased branching relative to untreated controls, and treatment with an EGF receptor (EGFR) antagonist prevented the increased branching induced by CCh. Gene expression studies indicated that both M1 and EGFR signaling were required to maintain epithelial progenitor cells in an undifferentiated state. CCh treatment increased expression of progenitor cell markers in cultured denervated adult SMGs, suggesting that CCh might be able to induce regenerative growth. The authors also noted that treating embryonic prostate explants with the EGFR antagonist and M1 inhibitor decreased progenitor cell marker expression, implying that this mechanism might be applicable to other branched organs. A Perspective by Rock and Hogan considers these results in the context of other types of branching morphogenesis and explores the possible implications of these findings for stimulating regeneration in patients whose salivary glands have been damaged by radiation therapy.

S. M. Knox, I. M. A. Lombaert, X. Reed, L. Vitale-Cross, J. S. Gutkind, M. P. Hoffman, Parasympathetic innervation maintains epithelial progenitor cells during salivary organogenesis. Science 329, 1645–1647 (2010). [Abstract] [Full Text]

J. R. Rock, B. L. M. Hogan, Branching takes nerve. Science 329, 1610–1611 (2010). [Summary] [Full Text]

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