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ScienceWeek
2004 18 June A3 NEUROBIOLOGY: ON MYELIN
The following points are made by C. Ffrench-Constant et al (Science 2004 304:688):
1) Myelination, the process by which glial cells ensheath the axons of neurons in layers of myelin, ensures the rapid conduction of electrical impulses in the nervous system. The formation of myelin sheaths is one of the most spectacular examples of cell-cell interaction and coordination in nature. Myelin sheaths are formed by the vast membranous extensions of glial cells: Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS). The axon is wrapped many times (like a Swiss roll) by these sheetlike membrane extensions to form the final myelin sheath or internode. Internodes can be as long as 1 mm and are separated from their neighbors by a short gap of 1 micron (the node of Ranvier). The concentration of voltage-dependent sodium channels in the axon membrane at the node, and the high electrical resistance of the multilayered myelin sheath, ensure that action potentials jump from node to node (a process termed "saltatory conduction").
2) The unique multilamellar architecture of the myelin sheath was recognized decades ago, yet the creation of this elaborate structure is still poorly understood. Most enigmatic of all, perhaps, is the control of the g ratio -- the precise relation between axon diameter and myelin sheath thickness (that is, the number of wraps around the axon). Just how is the myelinating glial cell instructed to make precisely the correct number of wraps? Transplantation of oligodendrocytes into nerve tracts containing axons of different sizes demonstrates that the number of wraps is determined by the axon and not by the glial cell, because the transplanted glial cells elaborate myelin sheaths appropriate for their new location (1). A key axonal signal for the regulation of myelin sheath thickness, the growth factor neuregulin (Ngr1), has been identified by Michailov et al (2).
3) Neuregulins are transmembrane and secreted growth factors encoded by four genes. Gene products of Nrg1 were first isolated in the early 1990s as potent mitogens (compounds that stimulate cell growth) for Schwann cells, ligands for the neu oncogene, and as stimulatory molecules for neuromuscular synapse formation. There are at least 15 different Nrg1 splice variants that fall into three classes according to their extracellular domain structures. All Nrg1s have an active epidermal growth factor (EGF)-like extracellular domain that can be secreted, tethered to the cell surface as part of a transmembrane isoform, or shed by proteolysis. In this way, the EGF-like domain of Nrg1s can be used for both long-range signaling and for short-range signaling through the ErbB receptor tyrosine kinases (3). Nrg1s may also act through other signaling pathways -- for example, an amino-terminal cysteine-rich domain present in Nrg1 type III is required for Schwann cell development (4).
4) The first evidence that Nrg1s might regulate myelin wrapping came from studies by Birchmeier et al (5), who deleted ErbB2 gene expression in mouse Schwann cells using a Cre/loxP strategy. The mice lacking Schwann cell ErbB2 had fewer myelin wraps around their PNS axons. In the newer study, Michailov et al (2) take this work a step further. They used a powerful transgenic approach to manipulate the levels of Nrg1 type III, which is normally expressed on the axon surface, and then examined the effect on myelination of the sciatic nerve by Schwann cells in the mouse PNS. They found that mice heterozygous for the null allele of the Nrg1 gene produced less neuregulin and had axons with a reduced number of myelin wraps. This resulted in a myelin sheath of reduced thickness and hence an increased g ratio. By contrast, animals heterozygous for the ErbB receptor exhibited no change in the number of wraps, demonstrating that the Nrg1 ligand (but not its ErbB receptor) is the limiting factor for myelination in vivo.
References (abridged):
1. M. L. Fanarraga, I. R. Griffiths, M. Zhao, I. D. Duncan, J. Comp. Neurol. 399, 94 (1998)
2. G. V. Michailov et al., Science 304, 700 (2004)
3. D. L. Falls, Exp. Cell Res. 284, 14 (2003)
4. A. N. Garratt, S. Britsch, C. Birchmeier, Bioessays 22, (2000)
5. A. N. Garratt, O. Voiculescu, P. Topilko, P. Charnay, C. Birchmeier, J. Cell Biol. 148, 1035 (2000)
Science http://www.sciencemag.org
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Related Material:
ON MYELIN PROTEINS AND NERVE REGENERATION
The following points are made by T.A. Watkins and B.A. Barres (Current Biology 2002 12:R654):
1) Unlike peripheral nervous system (PNS) axons, severed central nervous system (CNS) axons are unable to regenerate. Why do CNS and PNS axons differ so dramatically in their regenerative abilities? Differences in CNS and PNS glial cells appear to be crucial, as some CNS axons are able to regenerate through a peripheral nerve graft [1] . Axons are tightly wrapped by myelin membrane produced by oligodendrocytes in the CNS and Schwann cells in the PNS. Following axonal injury in the PNS, myelin is rapidly cleared by macrophages as the axons degenerate in a process known as Wallerian degeneration. In contrast, myelin is cleared much more slowly after CNS injury. This difference suggests that CNS myelin strongly inhibits regenerating axons, a possibility that was directly confirmed in elegant experiments by Martin Schwab and his colleagues [2].
2) An important first step towards identifying myelin inhibitors of axon regeneration was taken many years ago with the development of an anti-CNS myelin monoclonal antibody, IN-1, which promotes CNS regeneration and a limited degree of functional recovery in animal models [2] . Only in the last few years, however, have researchers begun to elucidate the key inhibitors and their receptors, uncovering a few surprises along the way. The target of the IN-1 antibody turned out to be Nogo, a reticulon homolog with three isoforms: Nogo-A is expressed primarily in oligodendrocytes, and the other two isoforms are more widely distributed (3). Interestingly, Nogo-A has two separate domains that can inhibit growing axons: the amino-terminal portion (Amino-Nogo), which is unique to Nogo-A, and a 66 amino acid peptide (Nogo-66) located between the two transmembrane regions, which is common to all isoforms.
3) How does Nogo inhibit regenerating axons? The functional receptor for Nogo-66, NgR, is a 473 amino acid protein with an attached glycosylphosphatidylinositol (GPI) lipid. This GPI linkage serves to anchor the protein to the outer surface of the cell membrane, where it can interact with its ligand. Binding studies and the effects of ectopic expression both confirmed that this protein is the functional receptor for Nogo-66 [4] . The expression patterns of Nogo and NgR are consistent with the interactions of these proteins at points of contact between axons and myelin, as well as at synapses [5] . It is unlikely, however, that NgR works alone: its lack of a transmembrane region implies the presence of an as yet unidentified transmembrane co-receptor that transduces the inhibitory signal.
4) In summary: Three different myelin proteins, Nogo, MAG, and OMgp, inhibit regenerating axons after CNS injury. New work reveals that they all share a common receptor and that blockade of this receptor promotes CNS repair and functional recovery.
References (abridged):
1. David S. and Aguayo A.J. (1981) Axonal elongation into peripheral nervous system 'bridges' after central nervous system injury in adult rats. Science, 214:931-933.
2. Caroni P. and Schwab M.E. (1988) Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron, 1:85-96.
3. Goldberg J.L. and Barres B.A. (2000) Nogo in nerve regeneration. Nature, 403:369-370.
4. Fournier A.E., GrandPre T. and Strittmatter S.M. (2001) Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature, 409:341-346.
5. Wang X., Chun S.J., Treloar H., Vartanian T., Greer C.A. and Strittmatter S.M. (2002) Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact. J. Neurosci., 22:5505-5515.
Current Biology http://www.current-biology.com
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Related Material:
NEUROBIOLOGY: GLIAL CELLS
The following points are made by Beth Stevens (Current Biology 2003 13:R469):
1) Santiago Ramon y Cajal (1852-1934), a Spanish histologist whose contributions on neuronal morphology and circuitry have dominated modern neuroscience, also made significant observations about glia, the non-neuronal cells in the brain. Yet his pioneering work on glial cells was all but ignored. Over a century ago, he recognized the great numbers of glia in the brain and their intimate association with neurons. Though their function was at that time a mystery, he predicted that glia must be doing more than simply filling the spaces between neurons.
2) Cajal was correct. Neuroscientists are now catching up and discovering that glia not only support a number of essential neuronal functions, but also actively communicate with neurons and with one another. By doing so, glia influence nervous system functions that have long been thought to be strictly under neuronal control.
3) In the human brain, glia outnumber neurons by a factor of ten, and today we can readily identify numerous glial cell types in the vertebrate nervous system based on their unique morphological and biochemical features. The myelinating glia --oligodendrocytes in the central nervous system (CNS) and Schwann cells in the periphery -- provide the insulating layers of myelin membrane around axons, which allow neural impulses to propagate rapidly over long distances. The other major category of glia are astrocytes, which have numerous forms and functions in the CNS.
4) Classical neurohistologists divided astrocytes into two main classes that are distinguished by morphology and location, and perhaps by function as well. Protoplasmic astrocytes found in grey matter are closely associated with synapses, while fibrillary (or fibrous) astrocytes in white matter contact nodes of Ranvier. Although most roles of astrocytes remain a great mystery, there is little doubt that they buffer ions and neurotransmitters in the extracellular space. Astrocytic processes also ensheath blood vessels, where they may help to regulate the development and maintenance of the blood-brain barrier by inducing tight junctions between endothelial cells. Moreover, astrocytes are, like most glia, major sources of extracellular matrix proteins, adhesion molecules, and neurotrophic factors. The role of these signals is still unclear, but they may help to promote neuronal growth, migration and survival.
Current Biology http://www.current-biology.com
ScienceWeek http://scienceweek.com
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