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Ying Xia, Esmond Geh, Qinghang Meng, Maureen Maureen Mongan, Jingcai Wang, Alvaro Puga; MAP3K1 Integrates Developmental Signals for Eyelid Closure. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1186.
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© ARVO (1962-2015); The Authors (2016-present)
Embryonic eyelid closure is an evolutionarily conserved morphogenetic process regulated by diverse signals. MAP3K1 is an intracellular kinase essential for eyelid closure. This study investigates the signaling mechanisms through which MAP3K1 orchestrates the morphogenetic event of eyelid closure.
Triple transgenic mice, RhoA(flox)/Le-Cre/Map3k1(+/-) were used to reveal the molecular interplay, whereas, the double transgenic mice, Map3k1(-/-)/AP-1-luc, were used to investigate the MAP3K1 downstream events, in eyelid development. Genetically manipulated mouse fibroblasts, transient transfection and luciferase reporter assays were used to investigate the endogenous and exogenous Map3k1 promoter activation by "eyelid morphogenetic factors", such as TGFα. Chromatin immunoprecipitation was performed to identify the transcription factors and chromatin signatures that mark the Map3k1 promoter activation.
We show that MAP3K1, highly expressed in developing eyelid epithelium, forms a regulatory axis with c-JUN that orchestrates morphogenesis by integrating two different networks of eyelid closure signals. One set of signals is initiated by a TGFα/EGFR-RhoA module that induces c-JUN expression and its phosphorylation-independent binding to the Map3k1 promoter, causing an increase in MAP3K1 expression. Knocking out RhoA in Map3k1 hemizygotes disturbs this network by decreasing MAP3K1 expression and delaying eyelid closure. The second set of signals is initiated by the MAP3K1 kinase that phosphorylates and activates a JNK-c-JUN module, leading to AP-1 transactivation and induction of its downstream genes, such as Pai-1. MAP3K1 ablation reduces AP-1 activity and PAI-1 expression both in cells and developing eyelids.
MAP3K1 is the focal point of a concerted circuit of signaling networks that control eyelid morphogenesis
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