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NEUROLOGY Glial Cells Critical for Peripheral Nervous System Health Communication with Glia Seems to Keep Nerve Cells Alive It is said that 90 percent of the world's problems are due to a lack of communication. A growing body of evidence suggests that the same may be true in the central nervous system, where the interaction between neuronal and non-neuronal cells has been implicated in both homeostasis and disease pathogenesis. Small diameter axons are grouped together by non-myelinating Schwann cells into structures called Remak bundles (left). When Gabriel Corfas (below) and coworkers blocked communication between these cells and neurons in mice, these bundles fell apart (right) and the animals lost feeling for hot and cold. The results suggest that non-myelinating Schwann cells play an essential role in the adult peripheral nervous system. (Images courtesy of Gabriel Corfas; photo by Graham Ramsay) In the peripheral nervous system, however, less is known about the necessity for communication between different cell types. It has been shown that cross-talk between neurons and non-myelinating Schwann cells is required during development, but the importance of this in the adult has not been established. In November's Nature Neuroscience, Gabriel Corfas, HMS associate professor of neurology at Children's Hospital, reports that such interactions are, indeed, essential in adult mice. "We have shown," said Corfas, "that non-myelinating Schwann cells play critical roles in peripheral neuronal function, in axon maintenance, and in neuronal survival." Corfas, together with the joint first authors on the paper, postdoctoral fellows Suzhen Chen and Carlos Rio; collaborators Ru-Rong Ji and Clifford Woolf of Massachusetts General Hospital; and Richard Coggeshall of the University of Texas at Galveston, came to this conclusion after blocking one of the main lines of communication between the two cell types, the neuregulin 1 signaling pathway. Fashioning Mouse Models Neuregulin 1 (NRG1), also known as glial growth factor, is secreted by neurons and activates the erbB tyrosine kinase receptors on glial cell surfaces. To inhibit this interaction in vivo, Chen and Rio took advantage of a dominant-negative form of erbB, which, when expressed in sufficient quantity, overwhelms wild-type receptors and quenches NRG1 signaling. To ensure this only occurs in adult non-myelinating Schwann cells, they used a promoter for glial fibrillary acidic protein (GFAP) to drive expression of the suppressor in transgenic mice. Expression of GFAP does not occur in myelinating Schwann cells and only reaches significant levels after birth, thus limiting production of the erbB suppressor, and hence inhibition of neuregulin signaling, to adult animals. "We have shown that non-myelinating Schwann cells play critical roles in peripheral neuronal function, in axon maintenance, and in neuronal survival." --Gabriel Corfas The authors generated several strains of transgenic mice that had robust expression of the dominant-negative erbB in the peripheral nervous system. When they examined one of these strains histologically, they found a huge increase (almost 20-fold) in the number of proliferating non-myelinating Schwann cells in the sciatic nerve, indicating that neuregulin signaling is essential to prevent the proliferation of these glia in the adult. This effect was surprising, since NGF1 signaling has always been considered progrowth. But many glia were also found to be dying by apoptosis, suggesting that they undergo cycles of proliferation and death. Corfas and colleagues, however, also noticed something else about these animals--they exhibited a gradual loss of sensory function. By five weeks old, the mice were at least six times slower than wild-type animals in reacting to a heat stimulus, and they were almost twice as slow as wild-type littermates in reacting to cold. In contrast, the animals' reaction to mechanical stimuli was normal, indicating that motor function, mediated by myelinated neurons, was still intact. Critical Conversation Could glial damage also affect the neurons? The non-myelinating Schwann cells group small diameter axons of C fiber neurons together into packets called Remak bundles. These are comprised of several axons surrounded by a single non-myelinating Schwann cell that squeezes its cytoplasm between and around the axons, keeping them close but separated. These striking structures suggest that the non-myelinating glia and the bundling itself could play important roles in the nerve; however, these have never been elucidated. When Corfas and colleagues examined the transgenic mice, they found that the condition of the Remak bundles varied with age. Sixteen days after birth, they looked morphologically normal, but by day 30, they had begun to fall apart. Furthermore, the number of unmyelinated axons in dorsal root ganglia dropped by about half (from 4,000 to 2,000 per root) in month-old mice, suggesting that whole neurons were being ablated. To test this hypothesis, the authors counted the C fiber neurons, finding that by day 60, there is a statistically significant drop in number. The two types of C fiber neurons, those expressing the protein TrkA and those expressing c-Ret, were reduced by 26 and 40 percent, respectively. Interdependence "There is a misconception that non-myelinating cells are there just to take over myelination whenever the need arises," Corfas ventured. His findings appear to debunk this theory and also negate the view that adult dorsal root ganglion sensory neurons do not depend on trophic support from the glia. Instead, the results suggest that there is an essential reciprocal interaction between non-myelinating Schwann cells and peripheral neurons. The latter, by releasing NRG1, promote survival of the glia and also prevent their proliferation. In return for neuregulin, the glia may be keeping up their part of the relationship by supplying neurons with glia-derived neurotrophic growth factor (GDNF). This protein is known to stimulate neuronal survival, and in the erbB-transgenic mice, Corfas found GDNF levels in the sciatic nerve were reduced by almost threefold in comparison to wild-type animals. More generally, the results suggest that disorders of the nervous system that have been blamed on neuronal dysfunction may actually be diseases of glial cells. "When we break glial- neuronal interactions, something goes wrong in the neurons," said Corfas. Glia therefore should be considered critical in the pathogenesis of a host of neurodegenerative diseases and peripheral neuropathies, such as diabetes and Fabry's disease, that manifest themselves by altered sensitivity to pain and other sensory stimuli. --Tom Fagan