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A. Takatori, R. Parthasarathy, M. Mongan, Y. Xia; Role of the MEKK1–JNK1 Pathway in Mouse Eyelid Morphogenesis . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3529.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Mouse embryonic eyelid closure is a developmental process involving complex signal interactions. MEK kinase 1 (MEKK1) is a mitogen–activated protein kinase kinase kinase, playing a critical role in mouse eyelid closure. The MEKK1–null mice are impaired in eyelid closure and they exhibit eye–open at birth (EOB) phenotype. The downstream effectors of MEKK1 are the c–Jun NH2–terminal kinases (JNKs), including JNK1 and JNK2. How MEKK1 differentially regulates JNK1 and JNK2 in eyelid closure has not been understood. This study is designed to use mouse eyelid development as readout to investigate the cross–talks and gene–dosage effects of the MEKK1–JNK1 and MEKK1–JNK2 pathways on eyelid morphogenesis. Methods: Mekk1–/–, Jnk1–/– and Jnk2–/– mice were backcrossed to C57BL/6 background. Intercrosses were carried out to generate Mekk1+/–Jnk1–/–, Mekk1+/–Jnk1+/– and Mekk1+/–Jnk2–/– mice. Sections of the developing eyes were analyzed by H&E staining and by immunohistochemistry using antibodies for phospho–c–Jun, phospho–JNK and phospho–extracellular signal–regulated protein kinase (ERK). Results: At birth, the Mekk1+/–Jnk1+/– and Mekk1+/–Jnk2–/– mice showed normal eyelid development and closure. In contrast, the Mekk1+/–Jnk1–/– mice displayed EOB similar to the Mekk1–/– mice. At embryonic days 16.5, a developmental stage when eyelid closure takes place, the Mekk1+/–Jnk1+/– fetuses showed a thin layer of eyelid epithelium that covered the ocular surface, whereas the Mekk1+/–Jnk1–/– fetuses had opened eyelids and fully exposed ocular surface. The MEKK1–JNK pathway activation results in the phosphorylation of transcription factor c–Jun. Abundant c–Jun phosphorylation was detected in the developing eyelid epithelium in Mekk1+/–Jnk1+/– fetuses, but very little, if any, c–Jun phosphorylation took place in Mekk1+/–Jnk1–/– fetuses. There were no differences, however, in JNK and ERK phosphorylation between Mekk1+/–Jnk1+/– and Mekk1+/–Jnk1–/– fetuses. Conclusions: We showed that the MEKK1 signal was mediated through the JNK pathways, in which JNK1 played a more critical role than JNK2 in the regulation of mouse embryonic eyelid closure. In the developing eyelid epithelium of the Mekk1+/–Jnk1–/– fetuses, one functional Mekk1 allele was apparently insufficient to cause c–Jun phosphorylation, suggesting that the remaining MEKK1–JNK2 activity could not fully compensate the specific roles provided by the MEKK1–JNK1 cascade. The distinct roles of the MEKK1–JNK1 and MEKK1–JNK2 pathways can be further studied by their functions in embryonic eyelid closure.
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