Abstract
Proper function of the nervous system depends on myelination. In peripheral nerves, Schwann cells (SCs) myelinate axons and the miRNA biogenesis pathway is required for developmental myelination and myelin maintenance. However, regulatory roles of this pathway at different stages of myelination are only partially understood. We addressed the requirement of the core miRNA biogenesis pathway components Dgcr8, Drosha, and Dicer in developing and adult SCs using mouse mutants with a comparative genetics and transcriptomics approach. We found that the microprocessor components Dgcr8 and Drosha are crucial for axonal radial sorting and to establish correct SC numbers upon myelination. Transcriptome analyses revealed a requirement of the microprocessor to prevent aberrantly increased expression of injury‐response genes. Those genes are predicted targets of abundant miRNAs in sciatic nerves (SNs) during developmental myelination. In agreement, Dgcr8 and Dicer are required for proper maintenance of the myelinated SC state, where abundant miRNAs in adult SNs are predicted to target injury‐response genes. We conclude that the miRNA biogenesis pathway in SCs is crucial for preventing inappropriate activity of injury‐response genes in developing and adult SCs.
Highlights
A system is defined as robust when it maintains its function in the presence of internal or external perturbations (Kitano, 2004)
We addressed the requirement of the core miRNA biogenesis pathway components Dgcr8, Drosha, and Dicer in developing and adult Schwann cells (SCs) using mouse mutants with a comparative genetics and transcriptomics approach
Given that the microprocessor mainly acts by giving rise to miRNAs that suppress target mRNAs, or in certain settings by directly binding and cleaving target mRNAs, we focused our analysis on the 533 genes robustly upregulated in Dgcr8 and Drosha cKO, qualifying them as potential primary effectors that drive the observed phenotypic differences (Figure 3c)
Summary
Proper function of the nervous system depends on myelination. In peripheral nerves, Schwann cells (SCs) myelinate axons and the miRNA biogenesis pathway is required for developmental myelination and myelin maintenance. We addressed the requirement of the core miRNA biogenesis pathway components Dgcr, Drosha, and Dicer in developing and adult SCs using mouse mutants with a comparative genetics and transcriptomics approach. Transcriptome analyses revealed a requirement of the microprocessor to prevent aberrantly increased expression of injury-response genes. Those genes are predicted targets of abundant miRNAs in sciatic nerves (SNs) during developmental myelination. Dgcr and Dicer are required for proper maintenance of the myelinated SC state, where abundant miRNAs in adult SNs are predicted to target injuryresponse genes.
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