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An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke

Abstract

Stroke is an age-related disease. Recovery after stroke is associated with axonal sprouting in cortex adjacent to the infarct. The molecular program that induces a mature cortical neuron to sprout a new connection after stroke is not known. We selectively isolated neurons that sprout a new connection in cortex after stroke and compared their whole-genome expression profile to that of adjacent, non-sprouting neurons. This 'sprouting transcriptome' identified a neuronal growth program that consists of growth factor, cell adhesion, axonal guidance and cytoskeletal modifying molecules that differed by age and time point. Gain and loss of function in three distinct functional classes showed new roles for these proteins in epigenetic regulation of axonal sprouting, growth factor–dependent survival of neurons and, in the aged mouse, paradoxical upregulation of myelin and ephrin receptors in sprouting neurons. This neuronal growth program may provide new therapeutic targets and suggest mechanisms for age-related differences in functional recovery.

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Figure 1: Experimental approach and laser capture microdissection of sprouting neurons after stroke.
Figure 2: Cellular pattern of ATRX, IGF1 and Lingo1 expression in the brain after stroke.
Figure 3: Quantitative connectional mapping.
Figure 4: ATRX function in post-stroke axonal sprouting.
Figure 5: IGF1 maintains neuronal viability after stroke.
Figure 6: Lingo1/NgR1 restricts cortical axonal sprouting after stroke.

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Acknowledgements

We thank S. Raike (University of Michigan) for help with obtaining NgR2 mutant mice. This research was funded by US National Institutes of Health NS045729, NS04733, NS049041, AHA 09SDG2310180 and 0525144Y; the US Department of Veterans Affairs; the Larry L Hillblom Foundation; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the American Federation of Aging Research.

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Authors

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S.L. designed and performed experiments, analyzed data and wrote the paper; J.J.O. developed cortical connectional mapping methodology and analyzed data; D.K. designed and performed experiments and analyzed data; S.V.K. developed a transgenic mouse first reported in this manuscript; C.J.D. and J.L.T. designed and performed the DRG in vitro studies; R.J.G. provided transgenic mice and reagents; G.C. and D.H.G. analyzed the microarray data; S.T.C. designed experiments, analyzed data and wrote the paper.

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Correspondence to S Thomas Carmichael.

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The authors declare no competing financial interests.

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Li, S., Overman, J., Katsman, D. et al. An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke. Nat Neurosci 13, 1496–1504 (2010). https://doi.org/10.1038/nn.2674

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