title: Deciphering gene expression program of MAP3K1 in mouse eyelid morphogenesis.
abstract: Embryonic eyelid closure involves forward movement and ultimate fusion of the upper and lower eyelids, an essential step of mammalian ocular surface development. Although its underlying mechanism of action is not fully understood, a functional mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is required for eyelid closure. Here we investigate the molecular signatures of MAP3K1 in eyelid morphogenesis. At mouse gestational day E15.5, the developmental stage immediately prior to eyelid closure, MAP3K1 expression is predominant in the eyelid leading edge (LE) and the inner eyelid (IE) epithelium. We used laser capture microdissection (LCM) to obtain highly enriched LE and IE cells from wild type and MAP3K1-deficient fetuses and analyzed genome-wide expression profiles. The gene expression data led to the identification of three distinct developmental features of MAP3K1. First, MAP3K1 modulated Wnt and Sonic hedgehog signals, actin reorganization, and proliferation only in LE but not in IE epithelium, illustrating the temporal-spatial specificity of MAP3K1 in embryogenesis. Second, MAP3K1 potentiated AP-2α expression and SRF and AP-1 activity, but its target genes were enriched for binding motifs of AP-2α and SRF, and not AP-1, suggesting the existence of novel MAP3K1-AP-2α/SRF modules in gene regulation. Third, MAP3K1 displayed variable effects on expression of lineage specific genes in the LE and IE epithelium, revealing potential roles of MAP3K1 in differentiation and lineage specification. Using LCM and expression array, our studies have uncovered novel molecular signatures of MAP3K1 in embryonic eyelid closure.
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, 3223 Eden Avenue, Kettering Laboratory, Suite 410, P.O. Box 670056, Cincinnati, OH 45267-0056, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Jin
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Qinghang
authors.initials: Q
authors.lastname: Meng
authors.forename: Vinicius
authors.initials: V
authors.lastname: Carreira
authors.forename: Neville N C
authors.initials: NN
authors.lastname: Tam
authors.forename: Esmond
authors.initials: E
authors.lastname: Geh
authors.forename: Saikumar
authors.initials: S
authors.lastname: Karyala
authors.forename: Shuk-Mei
authors.initials: SM
authors.lastname: Ho
authors.forename: Xiangtian
authors.initials: X
authors.lastname: Zhou
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D018076:DNA, Complementary / Q000378:metabolism; D005143:Eyelids / Q000196:embryology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D061346:Laser Capture Microdissection / Q000379:methods; D048728:MAP Kinase Kinase Kinase 1 / Q000096:biosynthesis* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D012313:RNA / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D050656:Transcription Factor AP-2 / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D026362:Serum Response Factor; D050656:Transcription Factor AP-2; D012313:RNA; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse