Connexin 43 is necessary for salivary gland branching morphogenesis and FGF10-induced ERK1/2 phosphorylation

Aya Yamada, Masaharu Futagi, Emiko Fukumoto, Kan Saito, Keigo Yoshizaki, Masaki Ishikawa, Makiko Arakaki, Ryoko Hino, Yu Sugawara, Momoko Ishikawa, Masahiro Naruse, Kanako Inoue, Takashi Nakamura, Satoshi Fukumoto

Research output: Contribution to journalArticle

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Abstract

Cell-cell interaction via the gap junction regulates cell growth and differentiation, leading to formation of organs of appropriate size and quality. To determine the role of connexin43 in salivary gland development, we analyzed its expression in developing submandibular glands (SMGs). Connexin43 (Cx43) was found to be expressed in salivary gland epithelium. In ex vivo organ cultures of SMGs, addition of the gap junctional inhibitors 18α-glycyrrhetinic acid (18α-GA) and oleamide inhibited SMG branching morphogenesis, suggesting that gap junctional communication contributes to salivary gland development. In Cx43-/- salivary glands, submandibular and sublingual gland size was reduced as compared with those from heterozygotes. The expression of Pdgfa, Pdgfb, Fgf7, and Fgf10, which induced branching of SMGs in Cx43-/- samples, were not changed as compared with those from heterozygotes. Furthermore, the blocking peptide for the hemichannel and gap junction channel showed inhibition of terminal bud branching. FGF10 induced branching morphogenesis, while it did not rescue the Cx43-/- phenotype, thus Cx43 may regulate FGF10 signaling during salivary gland development. FGF10 is expressed in salivary gland mesenchyme and regulates epithelial proliferation, and was shown to induce ERK1/2 phosphorylation in salivary epithelial cells, while ERK1/2 phosphorylation in HSY cells was dramatically inhibited by 18α-GA, a Cx43 peptide or siRNA. On the other hand, PDGF-AA and PDGF-BB separately induced ERK1/2 phosphorylation in primary cultured salivary mesenchymal cells regardless of the presence of 18α-GA. Together, our results suggest that Cx43 regulates FGF10-induced ERK1/2 phosphorylation in salivary epithelium but not in mesenchyme during the process of SMG branching morphogenesis.

Original languageEnglish
Pages (from-to)904-912
Number of pages9
JournalJournal of Biological Chemistry
Volume291
Issue number2
DOIs
Publication statusPublished - Jan 8 2016

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Connexin 43
Phosphorylation
Salivary Glands
Morphogenesis
Submandibular Gland
Glycyrrhetinic Acid
Gap Junctions
Mesoderm
Heterozygote
Epithelium
Sublingual Gland
Peptides
Organ Size
Organ Culture Techniques
Cell growth
Cell Communication
Small Interfering RNA
Cell Differentiation
Epithelial Cells
Phenotype

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Connexin 43 is necessary for salivary gland branching morphogenesis and FGF10-induced ERK1/2 phosphorylation. / Yamada, Aya; Futagi, Masaharu; Fukumoto, Emiko; Saito, Kan; Yoshizaki, Keigo; Ishikawa, Masaki; Arakaki, Makiko; Hino, Ryoko; Sugawara, Yu; Ishikawa, Momoko; Naruse, Masahiro; Inoue, Kanako; Nakamura, Takashi; Fukumoto, Satoshi.

In: Journal of Biological Chemistry, Vol. 291, No. 2, 08.01.2016, p. 904-912.

Research output: Contribution to journalArticle

Yamada, A, Futagi, M, Fukumoto, E, Saito, K, Yoshizaki, K, Ishikawa, M, Arakaki, M, Hino, R, Sugawara, Y, Ishikawa, M, Naruse, M, Inoue, K, Nakamura, T & Fukumoto, S 2016, 'Connexin 43 is necessary for salivary gland branching morphogenesis and FGF10-induced ERK1/2 phosphorylation', Journal of Biological Chemistry, vol. 291, no. 2, pp. 904-912. https://doi.org/10.1074/jbc.M115.674663
Yamada, Aya ; Futagi, Masaharu ; Fukumoto, Emiko ; Saito, Kan ; Yoshizaki, Keigo ; Ishikawa, Masaki ; Arakaki, Makiko ; Hino, Ryoko ; Sugawara, Yu ; Ishikawa, Momoko ; Naruse, Masahiro ; Inoue, Kanako ; Nakamura, Takashi ; Fukumoto, Satoshi. / Connexin 43 is necessary for salivary gland branching morphogenesis and FGF10-induced ERK1/2 phosphorylation. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 2. pp. 904-912.
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AU - Yoshizaki, Keigo

AU - Ishikawa, Masaki

AU - Arakaki, Makiko

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AU - Sugawara, Yu

AU - Ishikawa, Momoko

AU - Naruse, Masahiro

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