HB-EGF promotes epithelial cell migration in eyelid development
HB-EGF promotes epithelial cell migration in eyelid development
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DOI：
10.1242/dev.02030
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发表时间：
2005-10-01
期刊：
影响因子：
4.6
通讯作者：
Mekada, E
中科院分区：
文献类型：
--
作者：
Mine, N;Iwamoto, R;Mekada, E
肝素结合EGF样生长因子（HB-EGF）是EGF生长因子家族的一员，可结合并激活EGF受体（EGFR）和ERBB4。在这里，我们发现HB-EGF-EGFR信号参与眼睑发育。在妊娠晚期小鼠胚胎眼睑闭合期间，HB-EGF的表达仅限于迁移上皮的前沿尖端。HB-EGF缺失（HBdel/del）和分泌缺陷（HBuc/uc）突变胚胎都表现出眼睑闭合延迟，这是由于迁移上皮细胞中前缘延伸较慢和肌动蛋白束形成减少。在这些胚胎中未观察到细胞增殖的变化。此外，HBdel/del眼睑中EGFR和ERK的活性降低。HBdel/del小鼠与wave 2小鼠（一种半形EGFR突变株）的杂交表明，HB-EGF和EGFR在眼睑闭合中具有遗传相互作用。结合我们的数据显示，用EGFR特异性激酶抑制剂处理的胚胎表型HBdel/del胚胎，这些数据表明EGFR介导hb - egf依赖性眼睑闭合。最后，通过对TGF - α缺失小鼠和HB-EGF、TGF - α双缺失小鼠的闭眼情况分析，发现HB-EGF和TGF - α在闭眼过程中发挥了同等的作用和协同作用。这些结果表明，从前缘尖端分泌的可溶性HB-EGF激活了EGFR和ERK通路，并且在眼睑闭合过程中上皮片迁移的前缘延伸需要与TGF α协同作用。
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 TGF alpha-null mice and in HB-EGF and TGF alpha double null mice revealed that HB-EGF and TGF alpha 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 alpha is required for leading edge extension in epithelial sheet migration during eyelid closure.