D.H.R. is a Howard Hughes Medical Institute Investigator.
Oligodendrocyte PTEN is required for myelin and axonal integrity, not remyelination
Article first published online: 17 SEP 2010
Copyright © 2010 American Neurological Association
Annals of Neurology
Volume 68, Issue 5, pages 703–716, November 2010
How to Cite
Harrington, E. P., Zhao, C., Fancy, S. P. J., Kaing, S., Franklin, R. J. M. and Rowitch, D. H. (2010), Oligodendrocyte PTEN is required for myelin and axonal integrity, not remyelination. Ann Neurol., 68: 703–716. doi: 10.1002/ana.22090
- Issue published online: 28 OCT 2010
- Article first published online: 17 SEP 2010
- Manuscript Accepted: 19 MAY 2010
- Manuscript Revised: 16 APR 2010
- Manuscript Received: 26 JAN 2010
- National Multiple Sclerosis Translational Research partnership. Grant Number: TR3762-A1
- United Kingdom Multiple Sclerosis Society. Grant Number: 819/04
- National Institute of Health. Grant Number: R01 NS040511
- Medical Scientist Training Program at the University of California, San Francisco. Grant Number: NIGMS T32 GM07618
Repair of myelin injury in multiple sclerosis may fail, resulting in chronic demyelination, axonal loss, and disease progression. As cellular pathways regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN; eg, phosphatidylinositol-3-kinase [PI-3K]) have been reported to enhance axon regeneration and oligodendrocyte maturation, we investigated potentially beneficial effects of Pten loss of function in the oligodendrocyte lineage on remyelination.
We characterized oligodendrocyte numbers and myelin sheath thickness in mice with conditional inactivation of Pten in oligodendrocytes, Olig2-cre, Ptenfl/fl mice. Using a model of central nervous system demyelination, lysolecithin injection into the spinal cord white matter, we performed short- and long-term lesioning experiments and quantified oligodendrocyte maturation and myelin sheath thickness in remyelinating lesions.
During development, we observed dramatic hypermyelination in the corpus callosum and spinal cord. Following white matter injury, however, there was no detectable improvement in remyelination. Moreover, we observed progressive myelin sheath abnormalities and massive axon degeneration in the fasciculus gracilis of mutant animals, as indicated by ultrastructure and expression of SMI-32, amyloid precursor protein, and caspase 6.
These studies indicate adverse effects of chronic Pten inactivation (and by extension, activation PI-3K signaling) on myelinating oligodendrocytes and their axonal targets. We conclude that PTEN function in oligodendrocytes is required to regulate myelin thickness and preserve axon integrity. In contrast, PTEN is dispensable during myelin repair, and its inactivation confers no detectable benefit. Ann Neurol 2010