Dicer in Schwann Cells Is Required for Myelination and Axonal Integrity

Abstract

Dicer is responsible for the generation of mature micro-RNAs (miRNAs) and loading them into RNA-induced silencing complex (RISC). RISC functions as a probe that targets mRNAs leading to translational suppression and mRNA degradation. Schwann cells (SCs) in the peripheral nervous system undergo remarkable differentiation both in morphology and gene expression patterns throughout lineage progression to myelinating and nonmyelinating phenotypes. Gene expression in SCs is particularly tightly regulated and critical for the organism, as highlighted by the fact that a 50% decrease or an increase to 150% of normal gene expression of some myelin proteins, like PMP22, results in peripheral neuropathies. Here, we selectively deleted Dicer and consequently gene expression regulation by mature miRNAs from Mus musculus SCs. Our results show that in the absence of Dicer, most SCs arrest at the promyelinating stage and fail to start forming myelin. At the molecular level, the promyelinating transcription factor Krox20 and several myelin proteins [including myelin associated glycoprotein (MAG) and PMP22] were strongly reduced in mutant sciatic nerves. In contrast, the myelination inhibitors SOX2, Notch1, and Hes1 were increased, providing an additional potential basis for impaired myelination. A minor fraction of SCs, with some peculiar differences between sensory and motor fibers, overcame the myelination block and formed unusually thin myelin, in line with observed impaired neuregulin and AKT signaling. Surprisingly, we also found signs of axonal degeneration in Dicer mutant mice. Thus, our data indicate that miRNAs critically regulate Schwann cell gene expression that is required for myelination and to maintain axons via axon-glia interactions.

miR-221/222 promote Schwann cell proliferation and migration by targeting LASS2 following sciatic nerve injury

“…Several independent studies have established that miRNAs play a key role in SC differentiation, and each study indicates that the ablation of Dicer1 leads to SC overproliferation and aberrant myelination (Pereira et al, 2010;Yun et al, 2010). We now identify the role of miRNAs in wound-repair-initiating nerve reconstruction by orchestrating directed SC proliferation and migration.…”

“…Using microarray analysis, we found that abnormal expression of miRNA in dorsal root ganglia might illustrate the molecular mechanisms of nerve regeneration during the early phase after sciatic nerve transection (Zhou et al, 2011). The role of miRNA in nerve myelination was recently shown by independent studies of Dicer1-deficient oligodendrocytes and SCs (Dugas et al, 2010;Emery, 2010;Pereira et al, 2010;Yun et al, 2010). Despite the different molecular approaches for gene silencing in these studies, the ablation of Dicer1 (a key molecule in biogenesis of miRNA), as identified by each study, led to the common conclusion about glial overproliferation and aberrant myelination.…”

miR-9 inhibits Schwann cell migration by targeting CTHRC1 following sciatic nerve injury

“…Our previous study using microarray and deep sequencing showed that abnormal expression of miRNAs in dorsal root ganglia was involved in nerve regeneration after transection to rat sciatic nerves Zhou et al, 2011). The role of miRNAs in nerve myelination has been investigated by two independent studies on Dicer1-deficient Schwann cells (Pereira et al, 2010;Yun et al, 2010). It was further demonstrated that the majority of miRNAs expressed in mature Schwann cells could maintain the differentiated state of cells, but upon peripheral nerve injury, most of these miRNAs are downregulated allowing transcriptionally driven dedifferentiation of the Schwann cells (Viader et al, 2011).…”

Schwann Cell Myelination

“…Finally, miRNAs have been implicated as important, posttranscriptional regulators of myelination (Pereira et al 2012). This is compellingly indicated by conditional inactivation of DICER in Schwann cells during development, which results in the arrest of Schwann cells at the promyelinating stage (Bremer et al 2010;Pereira et al 2010;Yun et al 2010). An important question is the identity of the extrinsic signals that drives this transcriptional program, and that of axon wrapping.…”