How do Schwann cells know how much myelin to wrap around an axon during development? It's not a trivial problem—a small difference in myelin thickness can change signal transduction speed through the axon, with potentially devastating consequences for organism survival. According to a report published March 25 in ScienceExpress by German and U.S. researchers, axons use neuregulin-1 to signal how much myelin they require—a message that is relayed within the Schwann cells by erbB receptor tyrosine kinases.
With hints that white matter decay could be an early and contributing factor in Alzheimer's disease, myelin has become a focus of some AD researchers (for review, see Bartzokis, 2004). This is bringing attention to bear on molecules important for the formation of myelin, among them the many variants of neuregulin and erbB.
By creating mice with reduced gene dosages of the genes for neuregulin-1 or variations of erbB, as well as heterozygous combinations of these, Klaus-Armin Nave of the Max Planck Institute of Experimental Medicine in Gottingen, Germany, and his colleagues found that reductions in neuregulin-1 (type III) and erbB2 proteins were correlated with reduced myelination of peripheral axons. While the mice were behaviorally normal, nerve conduction velocity was reduced. Neuregulin-1 was determined to be the rate-limiting parameter, as reductions in gene dosage of erbB2 alone did not reduce myelin thickness.
Conversely, neuregulin-1 overexpression in transgenic mice resulted in thicker myelin around peripheral axons. "Although we cannot rule out the participation of additional axonal signals and growth factors, NRG-1 type III emerges as a critical regulator of Schwann cell myelin thickness," note the authors.
The links between myelin construction and maintenance and Alzheimer's disease remain murky. NRG-1 and the erbB family of receptors continue to be expressed in aging human brain, and it has been shown both that the distribution of expression changes in AD and that erbB4 and NRG-1 are associated with neuritic plaques (Chaudhury et al., 2003). In addition, Notch works some of its developmental effects via erbB2 and neuregulin signaling (see ARF related news story). We invite your speculations on these connections.—Hakon Heimer
- Bartzokis G. Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiol Aging. 2004 Jan;25(1):5-18; author reply 49-62. PubMed.
- Chaudhury AR, Gerecke KM, Wyss JM, Morgan DG, Gordon MN, Carroll SL. Neuregulin-1 and erbB4 immunoreactivity is associated with neuritic plaques in Alzheimer disease brain and in a transgenic model of Alzheimer disease. J Neuropathol Exp Neurol. 2003 Jan;62(1):42-54. PubMed.
- Michailov GV, Sereda MW, Brinkmann BG, Fischer TM, Haug B, Birchmeier C, Role L, Lai C, Schwab MH, Nave KA. Axonal neuregulin-1 regulates myelin sheath thickness. Science. 2004 Apr 30;304(5671):700-3. PubMed.