The Lin28/let-7 axis is critical for myelination in the peripheral nervous system.

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.