Combined KIT and FGFR2b Signaling Regulates Epithelial Progenitor Expansion during Organogenesis

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. •Combined KIT and FGFR2b signaling amplifies FGFR2b-dependent transcription•KIT/FGFR2b signaling during organogenesis expands distal KIT+ epithelial progenitors•Distal progenitors communicate with proximal progenitors via the neuronal niche•KIT+ progenitors maintain epithelial-neuronal communication during adult homeostasis Hoffman and colleagues demonstrate that combined KIT and fibroblast growth factor receptor 2b (FGFR2b) signaling expands the distal KIT+FGFR2b+ progenitor population in branching organs. This is important for continued branching morphogenesis because the KIT+FGFR2b+ progenitors produce neurotrophic factors to communicate with the neuronal niche to direct the ductal differentiation of proximal Keratin 5+ progenitors.