Microprocessor complex subunit DiGeorge syndrome critical region gene 8 (Dgcr8) is required for schwann cell myelination and myelin maintenance.
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.
From the Department of Neurology and Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 and.
Hsin-Pin
HP
Lin
From the Department of Neurology and Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 and.
Idil
I
Oksuz
Hunter James Kelly Research Institute, University at Buffalo, State University of New York, Buffalo, New York 14203.
Edward
E
Hurley
Hunter James Kelly Research Institute, University at Buffalo, State University of New York, Buffalo, New York 14203.
Lawrence
L
Wrabetz
From the Department of Neurology and Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 and r-awatramani@northwestern.edu.
Rajeshwar
R
Awatramani
D000818:Animals; D001369:Axons / Q000378:metabolism; D002454:Cell Differentiation; D003433:Crosses, Genetic; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D010641:Phenotype; D016601:RNA-Binding Proteins / Q000378:metabolism*; D043244:Ribonuclease III / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism*
C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
Schwann cells; cell differentiation; conditional knockouts; development; gene expression; gene regulation; microRNA (miRNA); mouse genetics; myelin; peripheral nervous system