Grainyhead-like factor Get1/Grhl3 regulates formation of the epidermal leading edge during eyelid closure.

Grainyhead transcription factors play an evolutionarily conserved role in regulating epidermal terminal differentiation. One such factor, the mammalian Grainyhead-like epithelial transactivator (Get1/Grhl3), is important for epidermal barrier formation. In addition to a role in barrier formation, Grainyhead genes play roles in closure of several structures such as the mouse neural tube and Drosophila wounds. Consistent with these observations, we found that Get1 knockout mice have an eye-open at birth phenotype. The failure of eyelid closure appears to be due to critical functions of Get1 in promoting F-actin polymerization, filopodia formation, and the cell shape changes that are required for migration of the keratinocytes at the leading edge during eyelid closure. The expression of TGFalpha, a known regulator of leading edge formation, is decreased in the eyelid tip of Get1(-/-) mice. Levels of phospho-EGFR and phospho-ERK are also decreased at the leading edge tip. Furthermore, in an organ culture model, TGFalpha can increase levels of phospho-EGFR and promote cell shape changes as well as leading edge formation in Get1(-/-) eyelids, indicating that in eyelid closure Get1 acts upstream of TGFalpha in the EGFR/ERK pathway.