Involvement of denervated midbrain-derived factors in the formation of ectopic cortico-mesencephalicprojection after hemispherectomy

Abstract

Neuronal remodeling after brain injury is essential for functional recovery. After unilateral cortical lesion, axons from the intact cortex ectopically project to the denervated midbrain to compensate for the lost function, but the underlying molecular mechanisms remain largely unknown. To address this issue, we examined gene expression profiles in denervated and intact mouse midbrains after hemispherectomy at P6, when ectopic contralateral projection occurs robustly. The analysis showed that various axon growth-related genes were upregulated in the denervated midbrain, and most of these genes are reportedly expressed by astrocytes or microglia. To identify the underlying molecules, the receptors for candidate upregulated molecules were knocked out in layer 5 projection neurons in the intact cortex, using the CRISPR/Cas9-mediated method, and axonal projection from the knocked-out cortical neurons was examined after hemispherectomy. We found that the ectopic projection was significantly reduced when integrin subunit beta 3 (Itgb3) or neurotrophic receptor tyrosine kinase 2 (Ntrk2, also known as TrkB) was knocked out. Overall, the present study suggests that midbrain-derived glial factors whose expression is upregulated after hemispherectomy are involved in lesion-induced remodeling of the cortico-mesencephalic projection.