Neuregulin-1 induces branching morphogenesis in the developing lung through a P13K signal pathway.
Neuregulin-1 (NRG-1) induces signal transduction through the activation of its receptor, a heterodimer of human epidermal growth factor receptors 2 and 3 (HER2/HER3). Signal transduction through this receptor/ligand system plays a critical role in the developing heart, mammary gland, and nervous systems. Previous studies showed that NRG-1-induced HER2 activation resulted in pulmonary epithelial cell proliferation in the human fetal lung. The authors hypothesized that NRG-1 further contributes to lung development and maturation by inducing branching morphogenesis. In the present study, the authors show that NRG-1, HER2, and HER3, but not HER4, are expressed in the developing mouse lung. Addition of NRG-1 to fetal lung explants increased lung branching morphogenesis by 32% (P < .05). This increase in branching was blocked by 2C4, an antibody directed against HER2 that inhibits its dimerization and subsequent NRG-1-induced signal transduction. To gain an understanding of the intracellular signaling pathways involved in NRG-1-induced branching morphogenesis, the authors specifically blocked the phosphatidylinositol-3 kinase (PI3K) and mitogen activation protein kinase (MAPK) pathways. Inhibition of PI3K signaling significantly decreased NRG-1-induced branching morphogenesis (P < .05). Inhibition of NRG-1-induced MAPK activation had no effect on explant branching morphogenesis. These data suggest that NRG-1, binding to the HER2/HER3 heterodimer receptor complex, induces pulmonary branching morphogenesis through HER2 activation of the PI3K pathway.
Liu
Jinbo
J
Department of Internal Medicine, Pulmonary and Critical Care Division, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio 44106, USA
Nethery
David
D
Kern
Jeffrey A
JA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D004247:DNA / Q000032:analysis; D004338:Drug Combinations; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000196:embryology; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects*; D020890:Neuregulin-1 / Q000378:metabolism* / Q000494:pharmacology; D009924:Organ Culture Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011247:Pregnancy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D004247:DNA; D004338:Drug Combinations; D005419:Flavonoids; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C481039:2C4 antibody; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one