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.
Highlights
MicroRNAs are crucial regulators of myelination in the peripheral nervous system (PNS)
Our data demonstrate that the let-7 family is functionally enriched during PNS myelination and suggest that the decline of lin28 homolog B (Lin28B) expression before myelination might be causal in this context
We found that Lin28B is a negative regulator of PNS myelination
Summary
MicroRNAs (miRNAs) are crucial regulators of myelination in the peripheral nervous system (PNS). Subsequent analyses revealed that let-7 miRNAs promote expression of the myelination-driving master transcription factor Krox[20] ( known as Egr2) through suppression of myelination inhibitory Notch signalling. Key regulators of let-7 expression are the RNAbinding proteins lin[28] homolog A and B (Lin28A and Lin28B) Both block let-7 biogenesis, and in turn, are targeted by let-7. Dicer-deficient SCs arrest their development when they engage with axons in a 1:1 relationship, known as the promyelinating stage Such mutant SCs fail to activate the correct myelination program and are unable to repress negative regulators of myelination, including Notch[1] and Sox[2]. Developmental downregulation of Lin28B and let-7 accumulation drives the onset of myelination by promoting Krox[20] expression through suppression of Notch signalling
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