Olig1 needed for remyelination

Newsdesk

Researchers in the USA and UK reportthat the transcription factor Olig1 isneeded in the nucleus for the differen-tiation of oligodendrocytes in adultmice, and therefore for remyelination(Science, 2004; 306: 2111–15). Thefinding may have an application in thetreatment of multiple sclerosis (MS).

“Olig1 and a close structuralhomologue, Olig 2, are both expressedduring the development of the nervoussystem”, explains US group leaderCharles Stiles (Dana-Farber CancerInstitute, Boston, MA, USA). “Butwhereas Olig2 is essential for oligoden-drocyte and neuron specification duringthis period, Olig1 seems not to be—infact, no-one is sure what it does. Ourwork shows that Olig1 is certainlyneeded for any remyelination to occur.”

Stiles’ team used antibodies to locateOlig1 and Olig2 during the develop-ment and repair of the nervous system

in mice. Olig2 was found in the nucleiof CNS cells at all stages of white-matter development. However, nearlyall the Olig1 had moved from thenucleus to the cytoplasm by 2 weeksafter birth, the developmental stage atwhich progenitor cells differentiate intomyelin-basic-protein-positive oligo-dendrocytes.

When the UK research group(University of Cambridge) examinedmice in which demyelination had beenchemically induced, Olig1 was found inthe nucleus of cells in earlyremyelinating lesions, as well as in theremyelinating cerebral lesions in post-mortem brain tissue from patients whohad MS. These findings suggest thatrepetition of Olig1’s localisation in thenucleus as seen during developmentmight be needed for repair. Indeed, inrepaired tissue, Olig1 was again foundin the cytoplasm.

“However, Olig1–/– mice—whichundergo largely normal myelinationduring development—were unable toremyelinate”, explains Stiles. “When[we followed] oligodendrocytematuration in demyelinated Olig1knockout mice, the progenitors ofthese cells were unable to differentiate.So, it seems that although Olig1 is not needed for oligodendrocytedifferentiation during development, itis required for remyelination, and it hasto be located in the nucleus if the signalto mature is to be understood.”

“It’s not yet clear whether there is anyfailure of the Olig1 system in MS thatmight hinder remyelination”, remarksPeter Dowling (New Jersey MedicalSchool, East Orange, NJ, USA). “If thereis, this might offer new therapeutictargets.”

Adrian Burton

80 http://neurology.thelancet.com Vol 4 February 2005

Olig1 needed for remyelination

The recent finding that adult neuralstem cells in the subventricular zone arederived from radial glia could haveimplications for the therapeutic use ofstem cells.

To test the hypothesis that radial gliain the neonatal brain produce theneurogenic astrocytes found in theadult subventricular zone, ArturoAlvarez-Buylla (Department ofNeurological Surgery, University ofCalifornia, San Francisco, USA) andcolleagues traced the progeny of radialglia in newborn mice (Proc Natl Acad SciUSA 2004; 101: 17528–32).

“We tagged a subpopulation of radialglia in the neonatal lateral ventricle andshowed that these cells produce all ofthe major brain-cell types, includingneurons, astrocytes, and oligoden-drocytes”, Alvarez-Buylla told TheLancet Neurology. “More importantly,we showed that neonatal radial gliagive rise to the subventricular zoneastrocytes that produce neurons

throughout life in the adult brain.”Previous research suggested that the

brain has two separate lineages: one forneurons and another for glial cells. Inthe late 1980s, studies in adult birdssuggested that radial glia were notinvolved in the formation of glial cellsbut were the precursors of neurons,Alvarez-Buylla says. More recent studiesreport that radial glia in the developingbrains of rodents are also stem cells, andcells with glial characteristics have beenidentified as the primary precursors ofnew neurons in adult rodents. Althoughthese findings prompted a majorconceptual shift in the understandingof cell origin in the brain, the linkbetween embryonic and adult neuralstem cells was unknown.

The current study, Alvarez-Buyllasays, reveals the developmental originof adult neural stem cells and provides atechnique for targeting and modifyingthese cells genetically in mice.“Identifying the lineage of the primary

progenitors in the brain is very basicnew information that should help infuture attempts to use stem-celltherapy for brain repair”, Alvarez-Buyllaadds.

Magdalena Götz (GSF-NationalResearch Centre for Environment andHealth, Munich, Germany) comments,“The finding that adult neural stem cellsoriginate from radial glia at the borderbetween the dorsal and ventraltelencephalon develops the importantconcept of a continuous lineagerelationship between developmentalneurogenesis from radial glia and adultneurogenesis from a subset ofastrocytes.”

Positional specification of the radialglia ancestors may explain why only afew (not most) astrocytes become stemcells; this could be a new approach forendowing astrocytes with stem-cellpotential in brain lesions, Götz says.

Kathleen Wildasin

New role for radial glia