Journal
DEVELOPMENTAL BIOLOGY
Volume 255, Issue 1, Pages 178-191Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/S0012-1606(02)00047-7
Keywords
branching morphogenesis; salivary gland; submandibular gland; organ culture; phosphatidylinositol 3-kinase; phosphatidylinositol 3,4,5-trisphosphate; akt; inhibitors; mouse; time-lapse microscopy
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Funding
- Intramural NIH HHS [Z01 DE000525-15] Funding Source: Medline
- NIDCR NIH HHS [F32 DE014322-03, DE-14322, F32 DE014322-01, F32 DE014322, F32 DE014322-02] Funding Source: Medline
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The mouse submandibular gland (SMG) epithelium undergoes extensive morphogenetic branching during embryonic development as the first step in the establishment of its glandular structure. However, the specific signaling pathways required for SMG branching morphogenesis are not well understood. Using E13 mouse SMG organ cultures, we showed that inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), wortmannin and LY294002, substantially inhibited branching morphogenesis in SMG. Branching morphogenesis of epithelial rudiments denuded of mesenchyme was inhibited similarly, indicating that PI 3-kinase inhibitors act directly on the epithelium. Immunostaining and Western analysis demonstrated that the p85 isoform of PI 3-kinase is expressed in epithelium at levels higher than in the mesenchyme. A target of PI 3-kinase, Akt/protein kinase B (PKB), showed decreased phosphorylation at Ser(473) by Western analysis in the presence of PI 3-kinase inhibitors. The major lipid product of PI 3-kinase, phosphatidylinositol 3,4,5-trisphosphate (PIP3), was added exogenously to SMG via a membrane-transporting carrier in the presence of PI 3-kinase inhibitors and was found to stimulate cleft formation, the first step of branching morphogenesis. Together, these data indicate that PI 3-kinase plays a role in the regulation of epithelial branching morphogenesis in mouse SMG acting through a PIP3 pathway. (C) 2003 Elsevier Science (USA). All rights reserved.
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