Abstract
We investigated the role of a key component of the Microprocessor complex, DGCR8, in the regulation of myelin formation and maintenance. We found that conditionally ablating Dgcr8 in Schwann cells (SCs) during development results in an arrest of SC differentiation. Dgcr8 conditional knock-out (cKO) SCs fail to form 1:1 relationships with axons or, having achieved this, fail to form myelin sheaths. The expression of genes normally found in immature SCs, such as sex-determining region Y-box 2 (Sox2), is increased in Dgcr8 cKO SCs, whereas the expression of myelin-related genes, including the master regulatory transcription factor early growth response 2 (Egr2), is decreased. Additionally, expression of a novel gene expression program involving sonic hedgehog (Shh), activated de novo in injured nerves, is elevated in Dgcr8 cKOs but not in Egr2 null mice, a model of SC differentiation arrest, suggesting that the injury-related gene expression program in Dgcr8 cKOs cannot be attributed to differentiation arrest. Inducible ablation of Dgcr8 in adult SCs results in gene expression changes similar to those found in cKOs, including an increase in the expression of Sox2 and Shh. Analyses of these nerves mainly reveal normal myelin thickness and axon size distribution but some dedifferentiated SCs and increased macrophage infiltration. Together our data suggest that Dgcr8 is responsible for modulation of gene expression programs underlying myelin formation and maintenance as well as suppression of an injury-related gene expression program.
Highlights
Dgcr8 regulates primary miRNA processing in the nucleus
In this study we conditionally knocked out Dgcr8 in developing and adult Schwann cells (SCs) to examine its role in SC myelination and myelin maintenance
We examined the expression of genes that are expressed by SCs in nerve injury models. qRT-PCR analysis for selected denervationassociated genes in control and Dgcr8 conditional knock-out (cKO) at P5 revealed the up-regulation of sonic hedgehog (Shh) and glial cell line-derived neurotrophic factor (Gdnf), Crabp1, tenascin C (Tnc), and SPARC-related modular calcium binding 1 (Smoc1)
Summary
Dgcr regulates primary miRNA processing in the nucleus. Results: Conditionally ablating Dgcr in Schwann cells during development or in adulthood causes defects in myelin formation and gene expression characteristic of immature and denervated (injured) Schwann cells. The novel findings of this study are that (i) Dcgr cKOs SCs are stalled in differentiation, like Dicer cKOs [28], but the phenotype of Dgcr mutants appears to be more severe, (ii) a de novo injury-specific program is elevated in Dgcr mutants at a very early age, and (iii) ablation of Dgcr in adult SCs results in profound gene expression changes, including activation of the de novo injury-specific gene expression program as well as SC degeneration, the latter of which is not observed in equivalent Dicer mutants [28] These results suggest that Dgcr plays an important role in myelination and myelin maintenance and that Dgcr and Dicer, in addition to processing sequential steps in miRNA biogenesis, may have some distinct functions
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