title: MicroRNAs Enhance Keratinocyte Proliferative Capacity in a Stem Cell-Enriched Epithelium.
abstract: MicroRNAs are critical regulators of stem cell behavior. The miR-103/107 family is preferentially expressed in the stem cell-enriched corneal limbal epithelium and plays an important role in coordinating several intrinsic characteristics of limbal epithelial stem cells. To elucidate further the mechanisms by which miRs-103/107 function in regulating limbal epithelial stem cells, we investigate the global effects of miRs-103/107 on gene expression in an unbiased manner. Using antagomirs-103/107, we knocked down endogenous miRs-103/107 in keratinocytes and conducted an mRNA profiling study. We show that miRs-103/107 target mitogen-activated protein kinase kinase kinase 7 (MAP3K7) and thereby negatively regulate the p38/AP-1 pathway, which directs epithelial cells towards a differentiated state. Pharmacological inhibition of p38 increases holoclone colony formation, a measure of proliferative capacity. This suggests that the negative regulation of p38 by miRs-103/107 contributes to enhanced proliferative capacity, which is a hallmark of stem cells. Since miRs-103/107 also promote increased holoclone colony formation by regulating JNK activation through non-canonical Wnt signaling, we believe that this microRNA family preserves "stemness" by mediating the crosstalk between the Wnt/JNK and MAP3K7/p38/AP-1 pathways.
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Jong Kook
authors.initials: JK
authors.lastname: Park
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Wending
authors.initials: W
authors.lastname: Yang
authors.affiliation: Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Julia
authors.initials: J
authors.lastname: Katsnelson
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Lavker
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Han
authors.initials: H
authors.lastname: Peng
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D016850:Limbus Corneae / Q000166:cytology; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C555364:MIRN103 microRNA, mouse; C555365:MIRN107 microRNA, mouse