title: Shh/Ptch and EGF/ErbB cooperatively regulate branching morphogenesis of fetal mouse submandibular glands.
abstract: The hedgehog family includes Sonic hedgehog (Shh), Desert hedgehog, and Indian hedgehog, which are well known as a morphogens that play many important roles during development of numerous organs such as the tongue, pancreas, kidney, cartilage, teeth and salivary glands (SMG). In Shh null mice, abnormal development of the salivary gland is seen after embryonic day 14 (E14). Shh also induced lobule formation and lumen formation in acini-like structures in cultured E14 SMG. In this study, we investigated the relationship between Shh and epidermal growth factor (EGF)/ErbB signaling in developing fetal mouse SMG. Administration of Shh to cultured E13 SMG stimulated branching morphogenesis (BrM) and induced synthesis of mRNAs for EGF ligands and receptors of the ErbB family. Shh also stimulated activation of ErbB signaling system such as ERK1/2. AG1478, a specific inhibitor of ErbB receptors, completely suppressed BrM and activation of EGF/ErbB/ERK1/2 cascade in E13 SMGs cultured with Shh. The expressions of mRNA for Egf in mesenchyme and mRNA for Erbb1, Erbb2 and Erbb3 in epithelium of E13 SMG were specifically induced by administration of Shh. These results show that Shh stimulates BrM of fetal mouse SMG, at least in part, through activation of the EGF/ErbB/ERK1/2 signaling system.
authors.affiliation: Department of Pharmacology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizukoshi
authors.affiliation: Department of Pharmacology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Koyama
authors.affiliation: Department of Pharmacology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Department of Pharmacy, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081, PR China.
authors.forename: Liguang
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Matsuura
authors.affiliation: Department of Pharmacology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan. Electronic address: matasan@dent.asahi-uac.jp.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kashimata
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics / Q000494:pharmacology*; D008813:Mice, Inbred ICR; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009024:Morphogenesis / Q000187:drug effects; D009924:Organ Culture Techniques; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013363:Submandibular Gland / Q000196:embryology / Q000378:metabolism*
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D053823:Hedgehog Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C000606240:Ptch1 protein, mouse; C000607800:ErbB3 protein, mouse; C524056:Erbb2 protein, mouse; C535148:Mapk1 protein, mouse
keywords: Branching morphogenesis; EGF; EGF receptor; Epithelio-mesenchymal interaction; Salivary gland; Shh