Oligodendrocyte PTEN is required for myelin and axonal integrity, not remyelination.
OBJECTIVE
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.


METHODS
We characterized oligodendrocyte numbers and myelin sheath thickness in mice with conditional inactivation of Pten in oligodendrocytes, Olig2-cre, Pten(fl/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.


RESULTS
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.


CONCLUSIONS
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.
Harrington
Emily P
EP
Department of Pediatrics, University of California at San Francisco, San Francisco, CA 94143, USA.
Zhao
Chao
C
Fancy
Stephen P J
SP
Kaing
Sovann
S
Franklin
Robin J M
RJ
Rowitch
David H
DH
D000367:Age Factors; D000818:Animals; D001369:Axons / Q000201:enzymology* / Q000473:pathology; D001921:Brain / Q000473:pathology / Q000648:ultrastructure; D002461:Cell Line, Transformed; D003711:Demyelinating Diseases / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D008244:Lysophosphatidylcholines; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009413:Nerve Fibers, Myelinated / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D009836:Oligodendroglia / Q000201:enzymology* / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure
D008244:Lysophosphatidylcholines; D051059:PTEN Phosphohydrolase