Your spinal cord is a little thicker than a length of clothes line _ sayhalf an inch or less in diameter. Like a heavy-duty electric cable, it'swrapped in a spiral insulating tape called myelin.Myelin, a layered complex of lipid and protein, sheaths all but thetiniest axons of both the central and peripheral nervous systems. Itsfunction, says molecular neuroscientist John Roder, "is to facilitatesignal conduction down the axons."He told BioWorld Today, "If all the fibers in your spinal cord wereunmyelinated, you'd have to have a bundle of spinal nerves severalmeters thick to carry the same message-forwarding functions."Roder, who teaches molecular medical genetics at the University ofToronto, compared myelin's role in information transmission to that ofa supercomputer: "The smaller the chip, the greater the computingpower. Myelin allows you to pack in tremendously more units."People in whose nervous systems the myelin sheaths deteriorate anddisappear suffer from multiple sclerosis (MS). Their nerve impulses areprogressively disordered, particularly in vision, sensation and limbcontrol, leading eventually to paralysis.The space between a coiled myelin sheath and the periaxonal body itwraps around is measured in nanometers _ 12 to 14 nm, Roder said.The "glue" or spacer that fills this gap is generally thought to be aprotein called myelin-associated glycoprotein (MAG).Roder, has created a population of MAG-lacking mice to test thehypothesis that the protein's adhesive function is so vital that without itthere would be no myelination. He reported his experiment, titled"Myelination in the absence of myelin-associated glycoprotein," in theissue of Nature out today."Part of our finding is negative," he said, in an interview. "It shows thatMAG is not really involved in the initial stages of myelin formation.Therefore, one would do better to look at other proteins."Glass Is Half Full, Half Empty"On the other hand," he added, "what it points to in the positive sense isthe importance of this periaxonal region that's never been shownbefore."Roder added, "When we eliminated the MAG gene by gene targeting inembryonic stem cells, the resulting animals _ surprisingly, andcontrary to what everyone in the field might predict _ had normalmyelin. But they did display some subtle abnormalities."Anatomically, his knockout mice do have a loose coil of myelinwrapping round the axon, collapsing its "periaxonal cytoplasmiccollar." Behaviorally, they shudder slightly when faced with a physicalfeat.He and his team have reared six generations of these geneticallyengineered animals, with their MAG gene knocked out, but myelinintact, and observed their behavior to see if it betrays lack of myelinfunction. One gymnastic task involves a knockout's ability to traverse anarrow beam, or "challenge bar.""Even a trained observer might be hard-pressed to detect anydifference," Roder said. "The normal mice did that quite uneventfully.The transgenic ones sat in front of the bar's narrowest part for a longtime, and had what we call an 'intentional tremor.' The back part oftheir bodies trembled for a few seconds."He pointed out that "multiple sclerosis patients have a largeamplification of this small intentional tremor."Of the lines of research the Toronto team is now pursuing to furtherelucidate MAG and myelination, one aspect in particular "mightinterest the biotech side of things," Roder said. That is, "some peoplebelieve MAG could be an inhibitor of nerve regeneration."There are other candidate regrowth inhibitors around, he noted, "butthey aren't really panning out."He observed that his MAG-minus knockout mice are ideallyconstituted to test this hypothesis. "We could damage a nerve, and,lacking MAG, they would be better able than normal animals toregenerate."To create his MAG-less mice, Roder started with an original Toronto-grown embryonic stem cell (ESC) line he announced last year. "It camefrom the inner cell mass of a 31-2- -day-old blastocyst, and turned outto be superior for making mice with knockouts."So much so, he said, that he has filled more than 200 requests fromaround the world for his ESC line, "and sold it to two or three biotechcompanies, with more willing to buy it."For the MAG-free mouse line, he transfected the ESC culture byelectroporation with a targeting vector carrying the genomic DNA forthe 16-kiloDalton MAG gene.After culturing these constructs for a couple of days with 21-2- -daymouse embryos, he transferred them to the uteri of pseudopregnantmurine mothers, to complete gestation.A leading researcher in the myelin field, molecular developmentalbiologist Robert A. Lazzarini, had this to say of Toronto's stem-cellapproach:"It's taken about 10 years to get these techniques fully developed towhere they can be applied to almost any gene, and now, by God, we'rethere. It delivers to a mammal, the mouse, a kind of genetics that in thepast we've only been able to have in lower organisms."Lazzarini, who directs the Brookdale Center for Molecular Biology atNew York's Mt. Sinai Hospital, welcomed Roder's MAG findings forits "implications for research into multiple sclerosis." He told BioWorldToday that MAG is implicated in MS, "a disease in which myelin isstripped away," noting that MS patients have polyclonal antibodies thatrecognize MAG.Moreover, he suggested that the protein "also has implications forremyelination in the case of MS."On the down-side, Lazzarini regretted that Roder's knockout mouse issuch a subtle phenotype. "We had expected, or hoped for, perhaps,gross hypomyelination, shivering mice, an animal model for MS, andwe didn't get it _ which shows how little we know." n

-- David N. Leff Science Editor

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