{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:07:38Z","timestamp":1791270458865,"version":"4.1.0"},"reference-count":46,"publisher":"The Company of Biologists","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,1,15]]},"abstract":"<jats:p>Basal cells are multipotent airway progenitors that generate distinct epithelial cell phenotypes crucial for homeostasis and repair of the conducting airways. Little is known about how these progenitor cells expand and transition to differentiation to form the pseudostratified airway epithelium in the developing and adult lung. Here, we show by genetic and pharmacological approaches that endogenous activation of Notch3 signaling selectively controls the pool of undifferentiated progenitors of upper airways available for differentiation. This mechanism depends on the availability of Jag1 and Jag2, and is key to generating a population of parabasal cells that later activates Notch1 and Notch2 for secretory-multiciliated cell fate selection. Disruption of this mechanism resulted in aberrant expansion of basal cells and altered pseudostratification. Analysis of human lungs showing similar abnormalities and decreased NOTCH3 expression in subjects with chronic obstructive pulmonary disease suggests an involvement of NOTCH3-dependent events in the pathogenesis of this condition.<\/jats:p>","DOI":"10.1242\/dev.116855","type":"journal-article","created":{"date-parts":[[2015,1,9]],"date-time":"2015-01-09T01:41:46Z","timestamp":1420767706000},"page":"258-267","source":"Crossref","is-referenced-by-count":175,"title":["Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors"],"prefix":"10.1242","volume":"142","author":[{"given":"Munemasa","family":"Mori","sequence":"first","affiliation":[{"name":"Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E.","family":"Mahoney","sequence":"additional","affiliation":[{"name":"Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria R.","family":"Stupnikov","sequence":"additional","affiliation":[{"name":"Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus R.","family":"Paez-Cortez","sequence":"additional","affiliation":[{"name":"Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander D.","family":"Szymaniak","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xaralabos","family":"Varelas","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan B.","family":"Herrick","sequence":"additional","affiliation":[{"name":"Department of Developmental, Molecular, and Chemical Biology, School of Medicine, Tufts University, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Schwob","sequence":"additional","affiliation":[{"name":"Department of Developmental, Molecular, and Chemical Biology, School of Medicine, Tufts University, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wellington V.","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, NY 10032, USA"},{"name":"Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042608151047100_DEV116855C1","doi-asserted-by":"publisher","first-page":"3022","DOI":"10.1101\/gad.1477606","article-title":"Canonical notch signaling functions as a commitment switch in the epidermal lineage","volume":"20","author":"Blanpain","year":"2006","journal-title":"Genes Dev."},{"key":"2021042608151047100_DEV116855C2","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/j.stem.2008.08.001","article-title":"Notch signaling regulates mammary stem cell function and luminal cell-fate commitment","volume":"3","author":"Bouras","year":"2008","journal-title":"Cell Stem Cell"},{"key":"2021042608151047100_DEV116855C3","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1165\/ajrcmb\/2.1.51","article-title":"Cell kinetics of normal adult hamster bronchial epithelium in the steady state","volume":"2","author":"Breuer","year":"1990","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2021042608151047100_DEV116855C45","doi-asserted-by":"publisher","first-page":"e52886","DOI":"10.1371\/journal.pone.0052886","article-title":"Integrin Beta 1 suppresses multilayering of a simple epithelium","volume":"7","author":"Chen","year":"2012","journal-title":"PLoS One"},{"key":"2021042608151047100_DEV116855C5","doi-asserted-by":"publisher","first-page":"1857","DOI":"10.1002\/stem.1429","article-title":"Somatic loss of p53 leads to stem\/progenitor cell amplification in both mammary epithelial compartments, basal and luminal","volume":"31","author":"Chiche","year":"2013","journal-title":"Stem Cells"},{"key":"2021042608151047100_DEV116855C6","doi-asserted-by":"publisher","first-page":"3451","DOI":"10.1158\/0008-5472.CAN-12-3902","article-title":"Notch3 functions as a tumor suppressor by controlling cellular senescence","volume":"73","author":"Cui","year":"2013","journal-title":"Cancer Res."},{"key":"2021042608151047100_DEV116855C7","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.1038\/sj.onc.1206230","article-title":"Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice","volume":"22","author":"Dang","year":"2003","journal-title":"Oncogene"},{"key":"2021042608151047100_DEV116855C8","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1164\/ajrccm.150.1.7912988","article-title":"Cell proliferation in the bronchial mucosa of asthmatics and chronic bronchitics","volume":"150","author":"Demoly","year":"1994","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2021042608151047100_DEV116855C9","doi-asserted-by":"publisher","first-page":"2730","DOI":"10.1101\/gad.308904","article-title":"Notch3 is required for arterial identity and maturation of vascular smooth muscle cells","volume":"18","author":"Domenga","year":"2004","journal-title":"Genes Dev."},{"key":"2021042608151047100_DEV116855C10","first-page":"119","article-title":"Tracheal epithelium: cell kinetics and differentiation in normal rat tissue","volume":"15","author":"Donnelly","year":"1982","journal-title":"Cell Tissue Kinet."},{"key":"2021042608151047100_DEV116855C11","doi-asserted-by":"publisher","first-page":"5148","DOI":"10.1038\/onc.2008.229","article-title":"The many facets of Notch ligands","volume":"27","author":"D'Souza","year":"2008","journal-title":"Oncogene"},{"key":"2021042608151047100_DEV116855C12","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1038\/nature03589","article-title":"Notch signals control the fate of immature progenitor cells in the intestine","volume":"435","author":"Fre","year":"2005","journal-title":"Nature"},{"key":"2021042608151047100_DEV116855C13","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1083\/jcb.200708185","article-title":"Skin stem cells: rising to the surface","volume":"180","author":"Fuchs","year":"2008","journal-title":"J. Cell Biol."},{"key":"2021042608151047100_DEV116855C14","doi-asserted-by":"publisher","first-page":"22678","DOI":"10.1074\/jbc.M111.241224","article-title":"Activation dynamics and signaling properties of Notch3 receptor in the developing pulmonary artery","volume":"286","author":"Ghosh","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2021042608151047100_DEV116855C15","doi-asserted-by":"publisher","first-page":"12592","DOI":"10.1073\/pnas.1204710109","article-title":"Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways","volume":"109","author":"Guha","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608151047100_DEV116855C16","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.1242\/dev.029249","article-title":"Notch signaling promotes airway mucous metaplasia and inhibits alveolar development","volume":"136","author":"Guseh","year":"2009","journal-title":"Development"},{"key":"2021042608151047100_DEV116855C17","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.1073\/pnas.0510839103","article-title":"Dicer function is essential for lung epithelium morphogenesis","volume":"103","author":"Harris","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608151047100_DEV116855C18","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1002\/stem.680","article-title":"Novel stem\/progenitor cell population from murine tracheal submucosal gland ducts with multipotent regenerative potential","volume":"29","author":"Hegab","year":"2011","journal-title":"Stem Cells"},{"key":"2021042608151047100_DEV116855C19","doi-asserted-by":"crossref","first-page":"3913","DOI":"10.1242\/dev.127.18.3913","article-title":"Basic helix-loop-helix transcription factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium","volume":"127","author":"Ito","year":"2000","journal-title":"Development"},{"key":"2021042608151047100_DEV116855C20","doi-asserted-by":"publisher","first-page":"3111","DOI":"10.4161\/cc.10.18.17300","article-title":"\u0394Np63\u03b1 promotes cellular quiescence via induction and activation of Notch3","volume":"10","author":"Kent","year":"2011","journal-title":"Cell Cycle"},{"key":"2021042608151047100_DEV116855C21","first-page":"311","article-title":"Modulation of proliferating cell nuclear antigen in the bronchial epithelium of smokers modulation of proliferating cell nuclear antigen in the bronchial epithelium of smokers 1","volume":"10","author":"Khuri","year":"2001","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"2021042608151047100_DEV116855C22","doi-asserted-by":"publisher","first-page":"8051","DOI":"10.1158\/0008-5472.CAN-07-1022","article-title":"Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers","volume":"67","author":"Konishi","year":"2007","journal-title":"Cancer Res."},{"key":"2021042608151047100_DEV116855C23","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.cell.2009.03.045","article-title":"The canonical Notch signaling pathway: unfolding the activation mechanism","volume":"137","author":"Kopan","year":"2009","journal-title":"Cell"},{"key":"2021042608151047100_DEV116855C24","doi-asserted-by":"publisher","first-page":"4955","DOI":"10.1242\/dev.01384","article-title":"Role of p63 and basal cells in the prostate","volume":"131","author":"Kurita","year":"2004","journal-title":"Development"},{"key":"2021042608151047100_DEV116855C25","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/nm.2021","article-title":"Notch3 signaling promotes the development of pulmonary arterial hypertension","volume":"15","author":"Li","year":"2009","journal-title":"Nat. Med."},{"key":"2021042608151047100_DEV116855C26","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1038\/nm.2000","article-title":"Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers","volume":"15","author":"Lim","year":"2009","journal-title":"Nat. Med."},{"key":"2021042608151047100_DEV116855C27","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.devcel.2014.06.003","article-title":"The hippo pathway effector yap controls patterning and differentiation of airway epithelial progenitors","volume":"30","author":"Mahoney","year":"2014","journal-title":"Dev. Cell"},{"key":"2021042608151047100_DEV116855C28","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1165\/ajrcmb.10.6.8003339","article-title":"Cell number and distribution in human and rat airways","volume":"10","author":"Mercer","year":"1994","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2021042608151047100_DEV116855C29","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1242\/jcs.058669","article-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","volume":"123","author":"Morimoto","year":"2010","journal-title":"J. Cell Sci."},{"key":"2021042608151047100_DEV116855C30","doi-asserted-by":"publisher","first-page":"4365","DOI":"10.1242\/dev.083840","article-title":"Different assemblies of Notch receptors coordinate the distribution of the major bronchial Clara, ciliated and neuroendocrine cells","volume":"139","author":"Morimoto","year":"2012","journal-title":"Development"},{"key":"2021042608151047100_DEV116855C31","doi-asserted-by":"publisher","first-page":"8105","DOI":"10.1073\/pnas.1221216110","article-title":"P63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia","volume":"110","author":"Pignon","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608151047100_DEV116855C32","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1073\/pnas.0610770104","article-title":"Lung development and repair: contribution of the ciliated lineage","volume":"104","author":"Rawlins","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608151047100_DEV116855C33","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1146\/annurev-cellbio-100109-104040","article-title":"Epithelial progenitor cells in lung development, maintenance, repair, and disease","volume":"27","author":"Rock","year":"2011","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"2021042608151047100_DEV116855C34","doi-asserted-by":"publisher","first-page":"12771","DOI":"10.1073\/pnas.0906850106","article-title":"Basal cells as stem cells of the mouse trachea and human airway epithelium","volume":"106","author":"Rock","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608151047100_DEV116855C35","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.stem.2011.04.003","article-title":"Notch-dependent differentiation of adult airway basal stem cells","volume":"8","author":"Rock","year":"2011","journal-title":"Cell Stem Cell"},{"key":"2021042608151047100_DEV116855C36","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1634\/stemcells.2006-0442","article-title":"p66Shc\/Notch-3 interplay controls self-renewal and hypoxia survival in human stem\/progenitor cells of the mammary gland expanded in vitro as mammospheres","volume":"25","author":"Sansone","year":"2007","journal-title":"Stem Cells"},{"key":"2021042608151047100_DEV116855C46","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1164\/rccm.200705-795OC","article-title":"Control of mitotic spindle angle by the RAS-regulated ERK1\/2 pathway determines lung tube shape","volume":"333","author":"Tang","year":"2011","journal-title":"Science"},{"key":"2021042608151047100_DEV116855C37","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1164\/rccm.200705-795OC","article-title":"Down-regulation of the notch pathway in human airway epithelium in association with smoking and chronic obstructive pulmonary disease","volume":"179","author":"Tilley","year":"2009","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2021042608151047100_DEV116855C38","doi-asserted-by":"publisher","first-page":"29532","DOI":"10.1074\/jbc.M801565200","article-title":"Gamma-secretase activation of notch signaling regulates the balance of proximal and distal fates in progenitor cells of the developing lung","volume":"283","author":"Tsao","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2021042608151047100_DEV116855C39","doi-asserted-by":"publisher","first-page":"2297","DOI":"10.1242\/dev.034884","article-title":"Notch signaling controls the balance of ciliated and secretory cell fates in developing airways","volume":"136","author":"Tsao","year":"2009","journal-title":"Development"},{"key":"2021042608151047100_DEV116855C47","doi-asserted-by":"publisher","first-page":"3533","DOI":"10.1242\/dev.063727","article-title":"Notch signaling prevents mucous metaplasia in mouse conducting airways during postnatal development","volume":"138","author":"Tsao","year":"2011","journal-title":"Development"},{"key":"2021042608151047100_DEV116855C40","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1002\/stem.1059","article-title":"NOTCH1 is required for regeneration of Clara cells during repair of airway injury","volume":"30","author":"Xing","year":"2012","journal-title":"Stem Cells"},{"key":"2021042608151047100_DEV116855C41","doi-asserted-by":"publisher","first-page":"L45","DOI":"10.1152\/ajplung.90550.2008","article-title":"Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis","volume":"298","author":"Xu","year":"2010","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2021042608151047100_DEV116855C42","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/35043127","article-title":"P63 and P73: P53 mimics, menaces and more","volume":"1","author":"Yang","year":"2000","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021042608151047100_DEV116855C43","doi-asserted-by":"crossref","first-page":"L1315","DOI":"10.1152\/ajplung.00169.2002","article-title":"Growth and differentiation of mouse tracheal epithelial cells: selection of a proliferative population","volume":"6","author":"You","year":"2002","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2021042608151047100_DEV116855C44","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1002\/dvdy.23965","article-title":"Jagged1 is the major regulator of Notch-dependent cell fate in proximal airways","volume":"242","author":"Zhang","year":"2013","journal-title":"Dev. Dyn."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/142\/2\/258\/1838983\/dev116855.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/142\/2\/258\/1838983\/dev116855.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T12:48:31Z","timestamp":1619441311000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/142\/2\/258\/47084\/Notch3-Jagged-signaling-controls-the-pool-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,15]]},"references-count":46,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2015,1,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.116855","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2015,1,15]]}}}