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First published online 1 September 2005
doi: 10.1242/dev.02030

This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: dev.02030v1 132/19/4317    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in Development Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mine, N. Articles by Mekada, E. Search for Related Content PubMed PubMed Citation Articles by Mine, N. Articles by Mekada, E.

HB-EGF promotes epithelial cell migration in eyelid development

Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita, Osaka 565-0871, Japan

^* Author for correspondence (e-mail: riwamoto{at}biken.osaka-u.ac.jp)

Accepted 2 August 2005

Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of growth factors that binds to and activates the EGF receptor (EGFR) and ERBB4. Here, we show that HB-EGF-EGFR signaling is involved in eyelid development. HB-EGF expression is restricted to the tip of the leading edge of the migrating epithelium during eyelid closure in late gestation mouse embryos. Both HB-EGF null (HB^del/del) and secretion-deficient (HB^uc/uc) mutant embryos exhibited delayed eyelid closure, owing to slower leading edge extension and reduced actin bundle formation in migrating epithelial cells. No changes in cell proliferation were observed in these embryos. In addition, activation of EGFR and ERK was decreased in HB^del/del eyelids. Crosses between HB^del/del mice and waved 2 mice, a hypomorphic EGFR mutant strain, indicate that HB-EGF and EGFR interact genetically in eyelid closure. Together with our data showing that embryos treated with an EGFR-specific kinase inhibitor phenocopy HB^del/del embryos, these data indicate that EGFR mediates HB-EGF-dependent eyelid closure. Finally, analysis of eyelid closure in TGF-null mice and in HB-EGF and TGF double null mice revealed that HB-EGF and TGF contribute equally to and function synergistically in this process. These results indicate that soluble HB-EGF secreted from the tip of the leading edge activates the EGFR and ERK pathway, and that synergy with TGF is required for leading edge extension in epithelial sheet migration during eyelid closure.

Key words: HB-EGF, TGF, EGFR, ERK, Eyelid, Leading edge, Epithelial cell migration, Mouse

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