HB-EGF promotes epithelial cell migration in eyelid development

Abstract

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 (HBdel/del) and secretion-deficient(HBuc/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 HBdel/del eyelids. Crosses between HBdel/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 HBdel/del embryos, these data indicate that EGFR mediates HB-EGF-dependent eyelid closure. Finally, analysis of eyelid closure in TGFα-null mice and in HB-EGF and TGFα double null mice revealed that HB-EGF and TGFα 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 TGFα is required for leading edge extension in epithelial sheet migration during eyelid closure.

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

“…Using an in vivo assay we have shown that Scribble is essential for proper wound healing in the mouse embryo, likely through the regulation of directed epithelial cell migration. Consistent with this idea, the circletail mouse (a second Scribble mutant mouse) exhibits an eye open at birth phenotype, which is commonly associated with disruptions to known cell migration regulators such as epidermal growth factor receptor (EGFR) and c-Jun (Berkowitz et al, 1996;Zenz et al, 2003;Mine et al, 2005). Thus, both in vitro and in vivo data presented here supports a critical role for Scribble in regulating directed migration in mammalian epithelium.…”

c-Jun, at the crossroad of the signaling network

“…Besides MAP3K1, embryonic eyelid closure depends on signals derived from WNT, Sonic hedgehog, BMP/Activin, FGF and EGF (Luetteke et al, 1993;Mine et al, 2005;Gage et al, 2008;Huang et al, 2009). In addition, eyelid closure requires the participation of a number of intracellular signaling kinases, such as JNK, ROCK and CDH1, and nuclear transcription factors, such as c-Jun, Fra-2, FOXL2, SMAD and GRHL3 (McHenry et al, 1998;Li et al, 2003;Zenz et al, 2003;Zhang et al, 2003;Uda et al, 2004;Thumkeo et al, 2005;Takatori et al, 2008;Yu et al, 2008;Naoe et al, 2010).…”

Heparin‐binding epidermal growth factor‐like growth factor as a novel targeting molecule for cancer therapy

“…(21) HB-EGF gene expression has been demonstrated in a variety of tissues, predominantly the lung, heart, brain and skeletal muscle. (22) HB-EGF participates in a variety of physiological and pathological processes, (11) including wound healing, (23) eyelid formation, (24) blastocyst implantation, (25) retinoic acid-induced epidermal hyperplasia (26) and atherosclerosis. (27) Recently, HB-EGF knockout mice have been established.…”