title: Submandibular parasympathetic gangliogenesis requires sprouty-dependent Wnt signals from epithelial progenitors.
abstract: Parasympathetic innervation is critical for submandibular gland (SMG) development and regeneration. Parasympathetic ganglia (PSG) are derived from Schwann cell precursors that migrate along nerves, differentiate into neurons, and coalesce within their target tissue to form ganglia. However, signals that initiate gangliogenesis after the precursors differentiate into neurons are unknown. We found that deleting negative regulators of FGF signaling, Sprouty1 and Sprouty2 (Spry1/2DKO), resulted in a striking loss of gangliogenesis, innervation, and keratin 5-positive (K5+) epithelial progenitors in the SMG. Here we identify Wnts produced by K5+ progenitors in the SMG as key mediators of gangliogenesis. Wnt signaling increases survival and proliferation of PSG neurons, and inhibiting Wnt signaling disrupts gangliogenesis and organ innervation. Activating Wnt signaling and reducing FGF gene dosage rescues gangliogenesis and innervation in both the Spry1/2DKO SMG and pancreas. Thus, K5+ progenitors produce Wnt signals to establish the PSG-epithelial communication required for organ innervation and progenitor cell maintenance.
authors: Matrix and Morphogenesis Section, NIDCR, NIH, Bethesda, MD 20892, USA.
authors: Wendy M
authors: WM
authors: Knosp
authors: Matrix and Morphogenesis Section, NIDCR, NIH, Bethesda, MD 20892, USA; Department of Cell and Tissue Biology, UCSF, San Francisco, CA 94143, USA.
authors: Sarah M
authors: SM
authors: Knox
authors: Matrix and Morphogenesis Section, NIDCR, NIH, Bethesda, MD 20892, USA.
authors: Isabelle M A
authors: IM
authors: Lombaert
authors: Matrix and Morphogenesis Section, NIDCR, NIH, Bethesda, MD 20892, USA.
authors: Candace L
authors: CL
authors: Haddox
authors: Matrix and Morphogenesis Section, NIDCR, NIH, Bethesda, MD 20892, USA.
authors: Vaishali N
authors: VN
authors: Patel
authors: Matrix and Morphogenesis Section, NIDCR, NIH, Bethesda, MD 20892, USA. Electronic address: mhoffman@mail.nih.gov.
authors: Matthew P
authors: MP
authors: Hoffman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D005346:Fibroblast Growth Factors / Q000235:genetics; D005726:Ganglia, Parasympathetic / Q000166:cytology / Q000196:embryology*; D018628:Gene Dosage / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D053569:Keratin-15 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D020880:Neuregulins; D009474:Neurons / Q000166:cytology; D009924:Organ Culture Techniques; D038081:Organogenesis / Q000235:genetics / Q000502:physiology; D010179:Pancreas / Q000294:innervation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D012583:Schwann Cells / Q000378:metabolism; D013234:Stem Cells; D013363:Submandibular Gland / Q000294:innervation*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005346:Fibroblast Growth Factors; D047908:Intracellular Signaling Peptides and Proteins; D053569:Keratin-15; D008565:Membrane Proteins; D020880:Neuregulins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D051153:Wnt Proteins; C492053:Krt15 protein, mouse; C425468:Spry1 protein, mouse; C118389:Spry2 protein, mouse