BACE1 Processing of NRG1 Type III Produces a Myelin-Inducing Signal but Is Not Essential for the Stimulation of Myelination

Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Goettingen, Germany.
Glia (Impact Factor: 6.03). 02/2012; 60(2):203-17. DOI: 10.1002/glia.21255
Source: PubMed

ABSTRACT Myelin sheath thickness is precisely adjusted to axon caliber, and in the peripheral nervous system, neuregulin 1 (NRG1) type III is a key regulator of this process. It has been proposed that the protease BACE1 activates NRG1 dependent myelination. Here, we characterize the predicted product of BACE1-mediated NRG1 type III processing in transgenic mice. Neuronal overexpression of a NRG1 type III-variant, designed to mimic prior cleavage in the juxtamembrane stalk region, induces hypermyelination in vivo and is sufficient to restore myelination of NRG1 type III-deficient neurons. This observation implies that the NRG1 cytoplasmic domain is dispensable and that processed NRG1 type III is sufficient for all steps of myelination. Surprisingly, transgenic neuronal overexpression of full-length NRG1 type III promotes hypermyelination also in BACE1 null mutant mice. Moreover, NRG1 processing is impaired but not abolished in BACE1 null mutants. Thus, BACE1 is not essential for the activation of NRG1 type III to promote myelination. Taken together, these findings suggest that multiple neuronal proteases collectively regulate NRG1 processing.

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    • "In particular, NRG1 type III represented a reasonable candidate to study because it is thought to act as a biochemical sensor of axon calibre (Michailov et al., 2004). The NRG1 type III full-length protein is processed to its biologically active form (75 kDa) by proteolytic cleavage (Velanac et al., 2012). Developmental analysis of NRG1 isoforms revealed a clear correlation between the active form of NRG1 type III and the onset of myelin basic protein expression, a marker for myelination, in sciatic nerves (Supplementary Fig. 1). "
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