Role of integrins and neuregulins in axoglial interaction in central nervous system myelination

Abstract

Oligodendrocytes in the central nervous system (CNS) are responsible for wrapping axons with myelin in order to insulate them and allow for a faster conduction of the nervous impulse. The axonal signals that determine whether an axon is myelinated, and what regulates the number of wraps is still not fully understood. The importance of signals that initiate myelination is significant because they may point to novel therapies for Multiple Sclerosis, where remyelination prevents the axon degeneration that is thought to underlie chronic disease. Neuregulin 1 (Nrg1) has been identified as a key axonal signaling molecule that regulates myelin thickness and glial fate in the peripheral nervous system (PNS). In the PNS, neuregulin I type III is a necessary and sufficient signal that regulates axoglial interaction. The role of neuregulin in the CNS remains unclear and controversial. Integrins, the major family of extracellular matrix (ECM) receptors are involved in the regulation of many fundamental cellular functions. Interaction with a wide range of receptors including growth factor receptors is well described. Our lab showed that α6β1 integrin regulates oligodendrocyte survival signaling by amplification of neuregulin activity. We have found that mice expressing a dominant-negative β1 integrin (that reduces β1 integrin signaling independently of ligand binding) in myelinating oligodendrocytes require a larger axon diameter to initiate myelination. These results suggest that there are other signals in the axon that also contribute to initiation of myelination. We therefore hypothesized that β1 integrin and neuregulin act in concert and play a role in axoglial interactions that sense the axon size and initiate myelination. By crossing the dominant negative β1 integrin mice with heterozygous mice for neuregulin 1 and analyzing myelination, we have found that neuregulin does not enhance the phenotype previously described. This result together with previous reports that mice lacking NRG1, ErbB3 or ErbB4 (the neuregulin receptors expressed on oligodendrocytes) have normal CNS myelin sheaths demonstrates that neuregulin 1 is not required for CNS myelination. Interestingly, neuregulin 1 has been associated as a susceptibility gene in schizophrenia, a disease independently associated with myelin abnormalities (Davis et al., 2003; Hakak et al., 2001). Post-mortem brains of schizophrenic patients showed an increased level of neuregulin 1 type IV. We have analysed mice overexpressing neuregulin 1 type IV (Nrg1 type IV) and show that increased levels of neuregulin 1 type IV does not alter the brain morphology or myelin pattern and integrity. A possible explanation is that since neuregulin 1 type IV is human specific, the mice lack species-specific receptors or other neuregulins have compensatory equilibrium mechanism that are not destabilized by overexpression of neuregulin 1 type IV.