MicroRNA‐204/211 alters epithelial physiology

Abstract

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.

microRNAs and inherited retinal dystrophies

“…Mutation in miR-204 as the cause of the disease is consistent with the observation that miR-204 is preferentially expressed in multiple ocular tissues, including the retina, RPE, ciliary body, and lens (11)(12)(13). In addition, previous in vitro and in vivo studies in medaka fish suggested its important roles in the development and function of the retina (13,14), lens (13)(14)(15), and RPE (12).…”

MicroRNA deep-sequencing reveals master regulators of follicular and papillary thyroid tumors

“…Particularly noteworthy was the consistent miR-204 downregulation observed in both tumor sets, specifically associated with the presence of the BRAF mutation. The targets of this miRNA were predicted to impair several cellular processes, such as those maintaining epithelial physiology, 36 which could explain the relatively poor prognosis described for these patients. 37 Another interesting marker was miR-7, highly significantly associated with BRAF mutation when compared to normal thyroid tissues in tumor set 1, and with wild-type papillary carcinomas in the validation set.…”

Experimental Models for Study of Retinal Pigment Epithelial Physiology and Pathophysiology

“…In previous experiments we have used these primary cultures to determine the expression, polarization and function of plasma membrane transport proteins and identify specific signaling pathways that regulate RPE function [1][2][3][4][5][6][7][8][9][10][11] These characteristics as they are accumulated provide a validation set of properties that can be applied to each cell generation. The experiments summarized below identify the proteins that determine transepithelial fluid transport and the integrity of the paracellular pathway.…”