Though neurons are the obvious stars of the nervous system, glia are getting more attention lately as research uncovers their importance in keeping the CNS disease-free (see ARF related news story). Now, Gabriel Corfas and colleagues at Children's Hospital, Boston, report in the November Nature Neuroscience that non-myelinating Schwann cells (NMSC) are essential for a healthy adult peripheral nervous system, and that this interaction is driven in part by neuregulins released from the neuron.
The neuregulins are a complex family of growth factors (Falls, 2003). Neuregulin-1, in particular, has gained notoriety as a possible risk factor for schizophrenia Stefansson et al., 2002; Williams et al., 2003). In this study, joint first authors Suzhen Chen and Carlos Rio probed the role of neuregulin-1 in adult mice. They introduced a dominant-negative mutant of ErbB, the non-myelinating Schwann cell receptor for neuregulin. To ensure that the signaling pathway was only suppressed in adult animals, they placed the suppressor under control of the promoter for glial acid fibrillary protein; expression of the latter only reaches significant levels in the adult. ErbB is known to be essential for development of the peripheral nervous system, but its role in the developed PNS has never been elucidated.
When Chen and colleagues examined adult mice harboring the ErbB suppressor, they found that NMSCs were undergoing rampant proliferation. This in itself was a surprise because inhibition of the neuregulin pathway would be predicted to have the opposite effect. But in addition, the authors found that NMSCs were undergoing apoptosis, suggesting that blocking the pathway caused both proliferation and cell death. The mice also showed a gradual loss of sensory perception when tested for response to heat and cold. By five weeks, the animals were at least six times slower than normal animals in reaction to a heat stimulus, and twice as slow in response to cold. To understand this better the authors looked at the morphology of postganglionic axons, finding that the Remak bundles, those clusters of non-myelinated axons wrapped by a single NMSC, were completely disrupted. Furthermore, transgenic animals had about 30 percent fewer small fiber neurons than did wild type.
The findings indicate that cross-talk between NMSCs and neurons is crucial for maintaining the peripheral nervous system. Support for this comes from the fact that Chen found levels of glial-derived growth factor, which is normally released by the NMSCs and taken up by neurons, are almost three times lower in the transgenic animals. This also suggest that in diseases resulting in loss of peripheral sensory perception, for example, diabetes and Fabry's disease, there may be a glial component to pathogenesis.—Tom Fagan
- Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res. 2003 Mar 10;284(1):14-30. PubMed.
- Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet. 2002 Oct;71(4):877-92. PubMed.
- Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, Zammit S, O'Donovan MC, Owen MJ. Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Mol Psychiatry. 2003 May;8(5):485-7. PubMed.
- Chen S, Rio C, Ji RR, Dikkes P, Coggeshall RE, Woolf CJ, Corfas G. Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss. Nat Neurosci. 2003 Nov 1;6(11):1186-93. PubMed.