TY - JOUR
T1 - Axl-/- mice have delayed recovery and prolonged axonal damage following cuprizone toxicity
AU - Hoehn, Hannah J.
AU - Kress, Yvonne
AU - Sohn, Albert
AU - Brosnan, Celia F.
AU - Bourdon, Sarah
AU - Shafit-Zagardo, Bridget
N1 - Funding Information:
Special thanks to Dr. James Goldman at Columbia University for advice on the cuprizone model and valuable suggestions during manuscript preparation. We thank Dr. Ana Marie Cuervo for her expertise on macroautophagy. We gratefully acknowledge the contributions of Dr. William Stallcup (Bunham Insitiute) for providing the Ng2 antibody, and Dr. Michael Wegner at the Institut fuer Biochemie, Universitaet Erlangen-Nuernberg, Erlangen for his Sox10 antibody. We thank Dr. Greg Lemke, Salk Institute, La Jolla CA, for the Axl−/− mice, and the Tyro3−/− mice. We thank Dr. Cedric Raine and Dr. Herbert Shaumburg at Albert Einstein College of Medicine, for their overall expertise and advice. We thank Dr. Rani Sellers for her help embedding the corpus callosum. We acknowledge the help of Jason Weinger in creating figures, with statistical analysis and reading the manuscript. This work was supported by grants from the National Multiple Sclerosis Society RG 3020 and RG4046, (BS-Z) and RG3827A5 (CFB). Albert Sohn and Sarah Bourdon were participants in the Albert Einstein College of Medicine Summer Undergraduate Research Program (SURP).
PY - 2008/11/13
Y1 - 2008/11/13
N2 - Activation of the receptor tyrosine kinase Axl recruits signaling molecules that regulate cell growth and survival. To evaluate Axl's role in brain during cuprizone toxicity, mice were fed cuprizone and evaluated at 3-, 4-, and 6-week cuprizone treatment and 3- and 5-week post-cuprizone withdrawal. At 4-week cuprizone treatment, the corpora callosa of wildtype (WT) mice had robust Oil Red O+ staining indicative of ongoing phagocytosis. Axl-/- mice had minimal Oil Red O+ staining, fewer microglia, and significantly more TUNEL+/ASPA+ mature oligodendrocytes than the WT. At 6-week cuprizone treatment, there was significantly more Oil Red O+ staining in the Axl-/- corpora callosa than in the WT indicating a lag in the clearance of cellular and myelin debris. Relative to WT mice, there were fewer mature oligodendrocytes and significantly more SMI-32+ axons at 3-week post-cuprizone withdrawal, indicative of axonal damage in the Axl-/- corpora callosa. Electron microscopy determined that at 3-week post-cuprizone withdrawal the number of dystrophic axons and axons containing autophagosome-like vacuoles/mouse was increased in the Axl-/- mice relative to the WT mice. In Axl-/- corpora callosa, 5-week post-cuprizone withdrawal, the number of mature oligodendrocytes was comparable to the WT mice, but axons in the Axl-/- mice were SMI-32+, suggesting that Axl-/- mice have delayed clearance of apoptotic oligodendrocytes and myelin debris resulting in prolonged axonal damage and recovery from cuprizone toxicity.
AB - Activation of the receptor tyrosine kinase Axl recruits signaling molecules that regulate cell growth and survival. To evaluate Axl's role in brain during cuprizone toxicity, mice were fed cuprizone and evaluated at 3-, 4-, and 6-week cuprizone treatment and 3- and 5-week post-cuprizone withdrawal. At 4-week cuprizone treatment, the corpora callosa of wildtype (WT) mice had robust Oil Red O+ staining indicative of ongoing phagocytosis. Axl-/- mice had minimal Oil Red O+ staining, fewer microglia, and significantly more TUNEL+/ASPA+ mature oligodendrocytes than the WT. At 6-week cuprizone treatment, there was significantly more Oil Red O+ staining in the Axl-/- corpora callosa than in the WT indicating a lag in the clearance of cellular and myelin debris. Relative to WT mice, there were fewer mature oligodendrocytes and significantly more SMI-32+ axons at 3-week post-cuprizone withdrawal, indicative of axonal damage in the Axl-/- corpora callosa. Electron microscopy determined that at 3-week post-cuprizone withdrawal the number of dystrophic axons and axons containing autophagosome-like vacuoles/mouse was increased in the Axl-/- mice relative to the WT mice. In Axl-/- corpora callosa, 5-week post-cuprizone withdrawal, the number of mature oligodendrocytes was comparable to the WT mice, but axons in the Axl-/- mice were SMI-32+, suggesting that Axl-/- mice have delayed clearance of apoptotic oligodendrocytes and myelin debris resulting in prolonged axonal damage and recovery from cuprizone toxicity.
KW - Autophagy
KW - Axonal damage
KW - Copper toxin
KW - Myelination
KW - Oligodendrocyte maturation
KW - Phagocytosis
KW - Vesicle
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U2 - 10.1016/j.brainres.2008.08.076
DO - 10.1016/j.brainres.2008.08.076
M3 - Article
C2 - 18804096
AN - SCOPUS:54549123319
SN - 0006-8993
VL - 1240
SP - 1
EP - 11
JO - Brain research
JF - Brain research
ER -