title: Combined KIT and FGFR2b signaling regulates epithelial progenitor expansion during organogenesis.
abstract: Organ formation and regeneration require epithelial progenitor expansion to engineer, maintain, and repair the branched tissue architecture. Identifying the mechanisms that control progenitor expansion will inform therapeutic organ (re)generation. Here, we discover that combined KIT and fibroblast growth factor receptor 2b (FGFR2b) signaling specifically increases distal progenitor expansion during salivary gland organogenesis. FGFR2b signaling upregulates the epithelial KIT pathway so that combined KIT/FGFR2b signaling, via separate AKT and mitogen-activated protein kinase (MAPK) pathways, amplifies FGFR2b-dependent transcription. Combined KIT/FGFR2b signaling selectively expands the number of KIT+K14+SOX10+ distal progenitors, and a genetic loss of KIT signaling depletes the distal progenitors but also unexpectedly depletes the K5+ proximal progenitors. This occurs because the distal progenitors produce neurotrophic factors that support gland innervation, which maintains the proximal progenitors. Furthermore, a rare population of KIT+FGFR2b+ cells is present in adult glands, in which KIT signaling also regulates epithelial-neuronal communication during homeostasis. Our findings provide a framework to direct regeneration of branched epithelial organs.
authors.affiliation: Matrix and Morphogenesis Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Isabelle M A
authors.initials: IM
authors.lastname: Lombaert
authors.affiliation: Matrix and Morphogenesis Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Abrams
authors.affiliation: Department of Orthopedics & Rehabilitation, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Orthopedics & Rehabilitation, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Veraragavan P
authors.initials: VP
authors.lastname: Eswarakumar
authors.affiliation: Developmental Mechanisms Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Aditya J
authors.initials: AJ
authors.lastname: Sethi
authors.affiliation: Head & Neck Multidisciplinary Clinic, Helen F. Graham Cancer Center of Christiana Care, Newark, DE 19713, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Witt
authors.affiliation: Matrix and Morphogenesis Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D038081:Organogenesis / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012469:Salivary Glands / Q000196:embryology* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D051497:Receptor, Fibroblast Growth Factor, Type 2