title: Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) integrates developmental signals for eyelid closure.
abstract: Developmental eyelid closure is an evolutionarily conserved morphogenetic event requiring proliferation, differentiation, cytoskeleton reorganization, and migration of epithelial cells at the tip of the developing eyelid. Many signaling events take place during eyelid closure, but how the signals converge to regulate the morphogenetic process remains an open and intriguing question. Here we show that mitogen-activated protein kinase kinase kinase 1 (MAP3K1) highly expressed in the developing eyelid epithelium, forms with c-Jun, a regulatory axis that orchestrates morphogenesis by integrating two different networks of eyelid closure signals. A TGF-α/EGFR-RhoA module initiates one of these networks by inducing c-Jun expression which, in a phosphorylation-independent manner, binds to the Map3k1 promoter and causes an increase in MAP3K1 expression. RhoA knockout in the ocular surface epithelium disturbs this network by decreasing MAP3K1 expression, and causes delayed eyelid closure in Map3k1 hemizygotes. The second network is initiated by the enzymatic activity of MAP3K1, which phosphorylates and activates a JNK-c-Jun module, leading to AP-1 transactivation and induction of its downstream genes, such as Pai-1. MAP3K1 inactivation reduces AP-1 activity and PAI-1 expression both in cells and developing eyelids. MAP3K1 is therefore the nexus of an intracrine regulatory loop connecting the TGF-α/EGFR/RhoA-c-Jun and JNK-c-Jun-AP-1 pathways in developmental eyelid closure.
authors.affiliation: Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Esmond
authors.initials: E
authors.lastname: Geh
authors.forename: Qinghang
authors.initials: Q
authors.lastname: Meng
authors.forename: Maureen
authors.initials: M
authors.lastname: Mongan
authors.forename: Jingcai
authors.initials: J
authors.lastname: Wang
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takatori
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Alvaro
authors.initials: A
authors.lastname: Puga
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lang
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism; D005143:Eyelids / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D048728:MAP Kinase Kinase Kinase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D054460:rho-Associated Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein