title: The Lin28/let-7 axis is critical for myelination in the peripheral nervous system.
abstract: MicroRNAs (miRNAs) are crucial regulators of myelination in the peripheral nervous system (PNS). However, the miRNAs species involved and the underlying mechanisms are largely unknown. We found that let-7 miRNAs are highly abundant during PNS myelination and that their levels are inversely correlated to the expression of lin28 homolog B (Lin28B), an antagonist of let-7 accumulation. Sustained expression of Lin28B and consequently reduced levels of let-7 miRNAs results in a failure of Schwann cell myelination in transgenic mouse models and in cell culture. Subsequent analyses revealed that let-7 miRNAs promote expression of the myelination-driving master transcription factor Krox20 (also known as Egr2) through suppression of myelination inhibitory Notch signalling. We conclude that the Lin28B/let-7 axis acts as a critical driver of PNS myelination, in particular by regulating myelination onset, identifying this pathway also as a potential therapeutic target in demyelinating diseases.
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland.
authors.forename: Deniz
authors.initials: D
authors.lastname: Gökbuget
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Pereira
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Bachofner
authors.affiliation: Department of Biology, Institute of Agricultural Sciences, ETH Zurich, Universitaetsstrasse 2, 8092 Zurich, Switzerland.
authors.forename: Antonin
authors.initials: A
authors.lastname: Marchais
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland.
authors.forename: Constance
authors.initials: C
authors.lastname: Ciaudo
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
authors.affiliation: Department of Pediatric Oncology and Haematology, Children's Hospital Essen, 45122 Essen, Germany.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland.
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051767:Early Growth Response Protein 2 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D017933:Peripheral Nervous System / Q000378:metabolism*; D016601:RNA-Binding Proteins; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; C570876:Lin28b protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D051880:Receptors, Notch; C542687:mirnlet7 microRNA, mouse; D043244:Ribonuclease III