title: Canonical Notch signaling in the developing lung is required for determination of arterial smooth muscle cells and selection of Clara versus ciliated cell fate.
abstract: Lung development is the result of complex interactions between four tissues: epithelium, mesenchyme, mesothelium and endothelium. We marked the lineages experiencing Notch1 activation in these four cellular compartments during lung development and complemented this analysis by comparing the cell fate choices made in the absence of RBPjkappa, the essential DNA binding partner of all Notch receptors. In the mesenchyme, RBPjkappa was required for the recruitment and specification of arterial vascular smooth muscle cells (vSMC) and for regulating mesothelial epithelial-mesenchymal transition (EMT), but no adverse affects were observed in mice lacking mesenchymal RBPjkappa. We provide indirect evidence that this is due to vSMC rescue by endothelial-mesenchymal transition (EnMT). In the epithelium, we show that Notch1 activation was most probably induced by Foxj1-expressing cells, which suggests that Notch1-mediated lateral inhibition regulates the selection of Clara cells at the expense of ciliated cells. Unexpectedly, and in contrast to Pofut1-null epithelium, Hes1 expression was only marginally reduced in RBPjkappa-null epithelium, with a corresponding minimal effect on pulmonary neuroendocrine cell fate selection. Collectively, the primary roles for canonical Notch signaling in lung development are in selection of Clara cell fate and in vSMC recruitment. These analyses suggest that the impact of gamma-secretase inhibitors on branching in vitro reflect a non-cell autonomous contribution from endothelial or vSMC-derived signals.
authors.affiliation: Department of Developmental Biology and Division of Dermatology, Washington University School of Medicine, Box 8103, Saint Louis, MO 63110-1095, USA.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Morimoto
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Liu
authors.forename: Hui-Teng
authors.initials: HT
authors.lastname: Cheng
authors.forename: Niki
authors.initials: N
authors.lastname: Winters
authors.forename: David
authors.initials: D
authors.lastname: Bader
authors.forename: Raphael
authors.initials: R
authors.lastname: Kopan
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000166:cytology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002923:Cilia / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000072056:Transcription Factor HES-1; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014598:Uteroglobin / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D016212:Transforming Growth Factor beta; D014598:Uteroglobin; C489734:Hes1 protein, mouse; C556390:Scgb1a1 protein, mouse