title: Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung.
abstract: Prevailing dogma holds that cell-cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed. Mucociliary clearance in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor. In contrast to such situations in which cell fate decisions are made in rapidly dividing populations, cells of the homeostatic adult airway epithelium are long-lived, and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a therapeutic foundation. Our discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation.
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lafkas
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Shelton
authors.affiliation: Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Chiu
authors.affiliation: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Gladys
authors.initials: G
authors.lastname: de Leon Boenig
authors.affiliation: Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Stawicki
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Siltanen
authors.affiliation: Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Reichelt
authors.affiliation: Department of Translational Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Translational Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eastham-Anderson
authors.affiliation: Department of Discovery Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Moore
authors.affiliation: Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Meron
authors.initials: M
authors.lastname: Roose-Girma
authors.affiliation: Departments of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Chinn
authors.affiliation: Departments of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Julie Q
authors.initials: JQ
authors.lastname: Hang
authors.affiliation: Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Søren
authors.initials: S
authors.lastname: Warming
authors.affiliation: Department of Discovery Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jackson
authors.initials: J
authors.lastname: Egen
authors.affiliation: Department of Translational Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Cary
authors.initials: C
authors.lastname: Austin
authors.affiliation: Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Payandeh
authors.affiliation: Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Lowe
authors.affiliation: Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Siebel
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D058948:Cell Tracking; D054338:Cell Transdifferentiation / Q000187:drug effects; D002923:Cilia / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020397:Goblet Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008024:Ligands; D008168:Lung / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000906:Antibodies; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C490504:JAG2 protein, human; C000606274:Jag1 protein, mouse; C490503:Jag2 protein, mouse; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins