Microprocessor Complex Subunit DiGeorge Syndrome Critical Region Gene 8 (Dgcr8) Is Required for Schwann Cell Myelination and Myelin Maintenance

Lin, Hsin Pin; Oksuz, Idil; Hurley, Edward; Wrabetz, Lawrence; Awatramani, Rajeshwar

doi:10.1074/jbc.m115.636407

Cited by 33 publications

(41 citation statements)

References 92 publications

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“…The analysis identified 4091 genes of peripheral nerves that were occupied by H3K27me3 around the transcription start site (± 7 kb), including 532 genes that are normally induced (> 2 fold) after injury, and revealed the H3K27me3 enrichment at silent or low-expressed genes (RPKM= < 1) (Figure 4A and Supporting Information Table 1). For example, H3K27me3 was highly enriched at a silenced gene of peripheral nerves, sonic hedgehog ( Shh ) (Arthur-Farraj et al 2012; Lin et al 2015), and over 73% of H3K27me3-occupied genes were expressed at very low levels (RPKM < 5). Interestingly, H3K27me3 was also abundant at some highly expressed genes, such as desert hedgehog (Dhh), a signaling molecule required for the structural and functional integrity of the peripheral nerves (Parmantier et al 1999; Sharghi-Namini et al 2006).…”

Section: Resultsmentioning

confidence: 99%

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Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

Duong

Moran

et al. 2018

Glia

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The transition of differentiated Schwann cells to support of nerve repair after injury is accompanied by remodeling of the Schwann cell epigenome. The EED-containing polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 methylation and represses key nerve repair genes such as Shh, Gdnf and Bdnf, and their activation is accompanied by loss of H3K27 methylation. Analysis of nerve injury in mice with a Schwann cell-specific loss of EED showed the reversal of polycomb repression is required and a rate limiting step in the increased transcription of Neuregulin 1 (type I), which is required for efficient remyelination. However, mouse nerves with EED-deficient Schwann cells display slow axonal regeneration with significantly low expression of axon guidance genes, including Sema4f and Cntf. Finally, EED loss causes impaired Schwann cell proliferation after injury with significant induction of the Cdkn2a cell cycle inhibitor gene. Interestingly, PRC2 subunits and CDKN2A are commonly co-mutated in the transition from benign neurofibromas to malignant peripheral nerve sheath tumors (MPNST’s). RNA-seq analysis of EED-deficient mice identified PRC2-regulated molecular pathways that may contribute to the transition to malignancy in neurofibromatosis.

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Section: Resultsmentioning

confidence: 99%

“…Many injury-induced genes encode intercellular signaling molecules such as sonic hedgehog ( Shh ), which is silenced throughout Schwann cell development prior to injury (Lin et al 2015). Schwann cells in injured nerve induce genes encoding factors that promote axon survival and regeneration: e.g.…”

Section: Introductionmentioning

confidence: 99%

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

Duong

Moran

et al. 2018

Glia

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“…In addition, Shh gene, which is not normally expressed in SCs, is activated upon nerve injury. Lin et al suggested that Sox-2 and Shh were involved in adhesion in SCs [36]. The mRNA expression patterns of Dgcr8, Zeb2, Dixdc1, Sox2, Shh, Gpr126, and Birc2 detected by qRT-PCR were opposite to the MeDIP analysis data with significance ( p < 0.05).…”

Section: Discussionmentioning

confidence: 96%

“…Glenn and Talbot [35] found that Gpr126 was essential for SCs to initiate myelination and addressed the role of Gpr126 signaling in myelin maturation and maintenance. Dgcr8 is responsible for modulation of myelin formation and maintenance as well as suppression of an injury-related gene expression program in SCs [36]. Quintes et al [37] proved that Zeb2 is essential for Schwann cell differentiation, myelination, and nerve repair.…”

Section: Discussionmentioning

confidence: 99%

Comparison of DNA Methylation in Schwann Cells before and after Peripheral Nerve Injury in Rats

Zhou

Lin

Ren

et al. 2017

BioMed Research International

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This study aims to find the difference of genomewide DNA methylation in Schwann cells (SCs) before and after peripheral nerve system (PNS) injury by Methylated DNA Immunoprecipitation Sequencing (MeDIP-Seq) and seek meaningful differentially methylated genes related to repairment of injured PNS. SCs harvested from sciatic nerve were named as activated Schwann cells (ASCs), and the ones harvested from brachial plexus were named as normal Schwann cells (NSCs). Genomic DNA of ASCs and NSCs were isolated and MeDIP-Seq was conducted. Differentially methylated genes and regions were discovered and analyzed by bioinformatic methods. MeDIP-Seq analysis showed methylation differences were identified between ASCs and NSCs. The distribution of differentially methylated regions (DMRs) peaks in different components of genome was mainly located in distal intergenic regions. GO and KEGG analysis of these methylated genes were also conducted. The expression patterns of hypermethylated genes (Dgcr8, Zeb2, Dixdc1, Sox2, and Shh) and hypomethylated genes (Gpr126, Birc2) detected by qRT-PCR were opposite to the MeDIP analysis data with significance (p < 0.05), which proved MeDIP analysis data were real and believable. Our data serve as a basis for understanding the injury-induced epigenetic changes in SCs and the foundation for further studies on repair of PNS injury.

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“…We have recently found that let‐7 miRNAs drive the onset of myelination (Gökbuget et al, ), and loss of Dgcr8 or Dicer in SCs impaired this developmental process (Bremer et al, ; Lin, Oksuz, Hurley, Wrabetz, & Awatramani, ; Pereira et al, ; Verrier, Semple‐Rowland, Madorsky, Papin, & Notterpek, ; Yun et al, ). Dgcr8‐ablated SCs appeared to be more affected than Dicer‐ablated SCs, in line with potential additional functions of the microprocessor in myelination (Lin et al, ). Furthermore, aberrant expression of repair SC markers and failure of proper myelin maintenance were noted.…”

Section: Introductionmentioning

confidence: 99%

The miRNA biogenesis pathway prevents inappropriate expression of injury response genes in developing and adult Schwann cells

Gökbuget

Pereira

Opitz

et al. 2018

Glia

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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.

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Microprocessor Complex Subunit DiGeorge Syndrome Critical Region Gene 8 (Dgcr8) Is Required for Schwann Cell Myelination and Myelin Maintenance

Cited by 33 publications

References 92 publications

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

Comparison of DNA Methylation in Schwann Cells before and after Peripheral Nerve Injury in Rats

The miRNA biogenesis pathway prevents inappropriate expression of injury response genes in developing and adult Schwann cells

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