MicroRNA-204/211 alters epithelial physiology.
MicroRNA (miRNA) expression in fetal human retinal pigment epithelium (hfRPE), retina, and choroid were pairwise compared to determine those miRNAs that are enriched by 10-fold or more in each tissue compared with both of its neighbors. miRs-184, 187, 200a/200b, 204/211, and 221/222 are enriched in hfRPE by 10- to 754-fold compared with neuroretina or choroid (P<0.05). Five of these miRNAs are enriched in RPE compared with 20 tissues throughout the body and are 10- to 20,000-fold more highly expressed (P<0.005). miR-204 and 211 are the most highly expressed in the RPE. In addition, expression of miR-204/211 is significantly lower in the NCI60 tumor cell line panel compared with that in 13 normal tissues, suggesting the progressive disruption of epithelial barriers and increased proliferation. We demonstrated that TGF-beta receptor 2 (TGF-betaR2) and SNAIL2 are direct targets of miR-204 and that a reduction in miR-204 expression leads to reduced expression of claudins 10, 16, and 19 (message/protein) consistent with our observation that anti-miR-204/211 decreased transepithelial resistance by 80% and reduced cell membrane voltage and conductance. The anti-miR-204-induced decrease in Kir7.1 protein levels suggests a signaling pathway that connects TGF-betaR2 and maintenance of potassium homeostasis. Overall, these data indicate a critical role for miR-204/211 in maintaining epithelial barrier function and cell physiology.
Wang
Fei E
FE
National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-2510, USA.
Zhang
Connie
C
Maminishkis
Arvydas
A
Dong
Lijin
L
Zhi
Connie
C
Li
Rong
R
Zhao
Jing
J
Majerciak
Vladimir
V
Gaur
Arti B
AB
Chen
Shan
S
Miller
Sheldon S
SS
D001483:Base Sequence; D001813:Blood-Retinal Barrier / Q000502:physiology*; D045744:Cell Line, Tumor; D002829:Choroid / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D057167:Claudins / Q000235:genetics; D005333:Fetus; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics
D057167:Claudins; C489477:Kir7.1 channel; C549404:MIRN204 microRNA, human; C549405:MIRN211 microRNA, human; D035683:MicroRNAs; D024661:Potassium Channels, Inwardly Rectifying; D018125:Receptors, Transforming Growth Factor beta; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II