Publication Date:
2015-11-19
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lafkas, Daniel -- Shelton, Amy -- Chiu, Cecilia -- de Leon Boenig, Gladys -- Chen, Yongmei -- Stawicki, Scott S -- Siltanen, Christian -- Reichelt, Mike -- Zhou, Meijuan -- Wu, Xiumin -- Eastham-Anderson, Jeffrey -- Moore, Heather -- Roose-Girma, Meron -- Chinn, Yvonne -- Hang, Julie Q -- Warming, Soren -- Egen, Jackson -- Lee, Wyne P -- Austin, Cary -- Wu, Yan -- Payandeh, Jian -- Lowe, John B -- Siebel, Christian W -- England -- Nature. 2015 Dec 3;528(7580):127-31. doi: 10.1038/nature15715. Epub 2015 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Translational Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Discovery Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Departments of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26580007" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antibodies/immunology/pharmacology/*therapeutic use
;
Asthma/drug therapy/metabolism/pathology
;
Calcium-Binding Proteins/antagonists & inhibitors/immunology/metabolism
;
Cell Death/drug effects
;
Cell Division/drug effects
;
Cell Lineage/drug effects
;
Cell Tracking
;
*Cell Transdifferentiation/drug effects
;
Cilia/metabolism
;
Disease Models, Animal
;
Female
;
Goblet Cells/cytology/drug effects/pathology
;
Homeostasis/drug effects
;
Humans
;
Intercellular Signaling Peptides and Proteins/immunology/metabolism
;
Ligands
;
Lung/*cytology/drug effects/*metabolism
;
Male
;
Membrane Proteins/antagonists & inhibitors/immunology/metabolism
;
Mice
;
Mice, Inbred BALB C
;
Mice, Inbred C57BL
;
Receptors, Notch/*metabolism
;
Signal Transduction/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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