Peripheral myelin protein 22 is regulated post-transcriptionally by miRNA-29a.

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Glia. 2009 Jan 23. [Epub ahead of print]

Peripheral myelin protein 22 is regulated post-transcriptionally by

miRNA-29a.

Verrier JD, Lau P, Hudson L, Murashov AK, Renne R, Notterpek L.

Department of Neuroscience, College of Medicine, McKnight Brain

Institute, University of Florida, Gainesville, Florida.

Peripheral myelin protein 22 (PMP22) is a dose-sensitive, disease-

associated protein primarily expressed in myelinating Schwann cells.

Either reduction or overproduction of PMP22 can result in hereditary

neuropathy, suggesting a requirement for correct protein expression

for peripheral nerve biology.

PMP22 is post-transcriptionally regulated and the 3'untranslated

region (3'UTR) of the gene exerts a negative effect on translation.

MicroRNAs (miRNAs) are small regulatory molecules that function at a

post-transcriptional level by targeting the 3'UTR in a reverse

complementary manner.

We used cultured Schwann cells to demonstrate that alterations in the

miRNA biogenesis pathway affect PMP22 levels, and endogenous PMP22 is

subjected to miRNA regulation. GW-body formation, the proposed

cytoplasmic site for miRNA-mediated repression, and Dicer expression,

an RNase III family ribonuclease involved in miRNA biogenesis, are co-

regulated with the differentiation state of Schwann cells.

Furthermore, the levels of Dicer inversely correlate with PMP22,

while the inhibition of Dicer leads to elevated PMP22. Microarray

analysis of actively proliferating and differentiated Schwann cells,

in conjunction with bioinformatics programs, identified several

candidate PMP22-targeting miRNAs.

Here we demonstrate that miR-29a binds and inhibits PMP22 reporter

expression through a specific miRNA seed binding region. Over-

expression of miR-29a enhances the association of PMP22 RNA with

Argonaute 2, a protein involved in miRNA function, and reduces the

steady-state levels of PMP22.

In contrast, inhibition of endogenous miR-29a relieves the miRNA-

mediated repression of PMP22. Correlation analyses of miR-29 and

PMP22 in sciatic nerves reveal an inverse relationship, both

developmentally and in post-crush injury.

These results identify PMP22 as a target of miRNAs and suggest that

myelin gene expression by Schwann cells is regulated by miRNAs.