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2015 ; 29
(7
): 1067-79
Nephropedia Template TP
Mol Endocrinol
2015[Jul]; 29
(7
): 1067-79
PMID26038943
show ga
Pancreatic ?-cells are the body's sole source of circulating insulin and
essential for the maintenance of blood glucose homeostasis. Levels of up to 66
"disallowed" genes, which are strongly expressed and play housekeeping roles in
most other mammalian tissues, are unusually low in ?-cells. The molecular
mechanisms involved in repressing these genes are largely unknown. Here, we
explore the role in gene disallowance of microRNAs (miRNAs), a type of small
noncoding RNAs that silence gene expression at the posttranscriptional level and
are essential for ?-cell development and function. To selectively deplete miRNAs
from adult ?-cells, the miRNA-processing enzyme DICER was inactivated by deletion
of the RNase III domain with a tamoxifen-inducible Pdx1CreER transgene. In this
model, ?-cell dysfunction was apparent 2 weeks after recombination and preceded a
decrease in insulin content and loss of ?-cell mass. Of the 14 disallowed genes
studied, quantitative RT-quantitative real-time PCR revealed that 6 genes (Fcgrt,
Igfbp4, Maf, Oat, Pdgfra, and Slc16a1) were up-regulated (1.4- to 2.1-fold, P <
.05) at this early stage. Expression of luciferase constructs bearing the
3'-untranslated regions of the corresponding mRNAs in wild-type or DICER-null
?-cells demonstrated that Fcgrt, Oat, and Pdgfra are miRNA direct targets. We
thus reveal a role for miRNAs in the regulation of disallowed genes in ?-cells
and provide evidence for a novel means through which noncoding RNAs control the
functional identity of these cells independently of actions on ?-cell mass.
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