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

Abstract

The authors compare the whole-genome expression profiles of peri-infarct neurons that show axonal sprouting after stroke to their non-sprouting neighbors. They describe a 'sprouting transcriptome' and perform further gain- and loss-of-function studies, finding novel roles in sprouting for a DNA-modifying molecule, a growth factor, and inhibitory myelin receptors. 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.