MicroRNA-deficient Schwann cells display congenital hypomyelination.
MicroRNAs, by modulating gene expression, have been implicated as regulators of various cellular and physiological processes, including differentiation, proliferation, and cancer. Here, we study the role of microRNAs in Schwann cell (SC) differentiation by conditional removal of the microRNA processing enzyme Dicer1. We reveal that both male and female mice lacking Dicer1 in SC (Dicer1 conditional knock-outs) display a severe neurological phenotype resembling congenital hypomyelination. Ultrastructural analyses show that many SC lacking Dicer1 are stalled in differentiation at the promyelinating state and fail to myelinate axons. Gene expression analyses reveal a failure to extinguish genes characteristic of the undifferentiated state such as Sox2, Jun, and Ccnd1. Sox2 and Jun are well characterized negative regulators of SC differentiation. Consistent with Sox2/Jun maintenance, Egr2, a master regulator of the myelinating program, is drastically downregulated and likely accounts for the myelination defect. We posit a model wherein microRNAs are critical for downregulation of antecedent programs of gene expression. In SC differentiation, this is particularly relevant in the key developmental transition from a promyelinating to myelinating SC.
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Beth
B
Yun
Angela
A
Anderegg
Daniela
D
Menichella
Lawrence
L
Wrabetz
M Laura
ML
Feltri
Rajeshwar
R
Awatramani
D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000172:deficiency*; D003711:Demyelinating Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D004722:Endoribonucleases / Q000172:deficiency*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D007211:Indoles; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D012583:Schwann Cells / Q000473:pathology* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000473:pathology
C530105:Ccnd1 protein, mouse; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D007211:Indoles; D035683:MicroRNAs; D016755:Proto-Oncogene Proteins c-jun; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D019938:Cyclin D1; C007293:DAPI; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; D001973:Bromodeoxyuridine