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

Journal J. Neurosci. 42(5):749-761 (2021)
Title Involvement of denervated midbrain-derived factors in the formation of ectopic cortico-mesencephalic projection after hemispherectomy
Laboratory Cellular and Molecular Neurobiology Group

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, but the molecular mechanisms remain largely unknown. To address this issue, we examined gene expression profiles in denervated and intact mouse midbrains after hemispherectomy at early developmental stages using mice of either sex, 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 glial cells. 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 or neurotrophic receptor tyrosine kinase 2 (also known as TrkB) was knocked out. Overall, the present study suggests that denervated midbrain-derived glial factors contribute to lesion-induced remodeling of the cortico-mesencephalic projection via these receptors.SIGNIFICANCE STATEMENTAfter brain injury, compensatory neural circuits are established that contribute to functional recovery. However, little is known about the intrinsic mechanism which underlies the injury-induced remodeling. We found that after unilateral cortical ablation expression of axon-growth promoting factors is elevated in the denervated midbrain and is involved in the formation of ectopic axonal projection from the intact cortex. Evidence further demonstrated that these factors are expressed by astrocytes and microglia, which are activated in the denervated midbrain. Thus, our present study provides a new insight into the mechanism of lesion-induced axonal remodeling and further therapeutic strategies after brain injury.


Leechung Chang (1), Mayuko Masada (1), Masami Kojima (2, 3), Nobuhiko Yamamoto (1)

  1. Laboratory of Cellular and Molecular Neurobiology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
  2. Department of Applied Bioscience, Kanazawa Institute of Technology (KIT), 3-1 Yatsukaho, Hakusan, Ishikawa 924-0838, Japan.
  3. Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ikeda, Osaka 563-8577, Japan.
PubMed 34887319