title: Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells.
abstract: Our understanding of how stem cells are regulated to maintain appropriate tissue size and architecture is incomplete. We show that Yap (Yes-associated protein 1) is required for the actual maintenance of an adult mammalian stem cell. Without Yap, adult airway basal stem cells are lost through their unrestrained differentiation, resulting in the simplification of a pseudostratified epithelium into a columnar one. Conversely, Yap overexpression increases stem cell self-renewal and blocks terminal differentiation, resulting in epithelial hyperplasia and stratification. Yap overexpression in differentiated secretory cells causes them to partially reprogram and adopt a stem cell-like identity. In contrast, Yap knockdown prevents the dedifferentiation of secretory cells into stem cells. We then show that Yap functionally interacts with p63, the cardinal transcription factor associated with myriad epithelial basal stem cells. In aggregate, we show that Yap regulates all of the cardinal behaviors of airway epithelial stem cells and determines epithelial architecture.
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Internal Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Fallon
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
authors.forename: Srinivas Vinod
authors.initials: SV
authors.lastname: Saladi
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Internal Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Pardo-Saganta
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Villoria
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Internal Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mou
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Internal Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vinarsky
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Meryem
authors.initials: M
authors.lastname: Gonzalez-Celeiro
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Naveen
authors.initials: N
authors.lastname: Nunna
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Lida P
authors.initials: LP
authors.lastname: Hariri
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Camargo
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
authors.forename: Leif W
authors.initials: LW
authors.lastname: Ellisen
authors.affiliation: Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Pediatrics, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Internal Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: jrajagopal@partners.org.
authors.forename: Jayaraj
authors.initials: J
authors.lastname: Rajagopal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014132:Trachea / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse