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The Journal of Neuroscience, April 15, 2000, 20(8):2875-2886

Akt/Protein Kinase B Prevents Injury-Induced Motoneuron Death and Accelerates Axonal Regeneration

Kazuhiko Namikawa¹, Masaru Honma^{1, 2}, Koji Abe^{1, 3}, Masumi Takeda^{1, 4}, Khalil Mansur¹, Tatsuo Obata¹, Akiko Miwa^{5, 6}, Haruo Okado^{5, 6}, and Hiroshi Kiyama^{1, 6}

Departments of ¹ Anatomy, ² Dermatology,³ Psychiatry and Neurology, and ⁴ Ophthalmology, Asahikawa Medical College, Asahikawa, Hokkaido, 078-8510 Japan, ⁵ Department of Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, 183-8526 Japan, and ⁶ Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology, Kawaguchi, Saitama, 332-0012 Japan

Motoneurons require neurotrophic factors for their survival and axonal projection during development, as well as nerve regeneration. By using the axotomy-induced neuronal death paradigm and adenovirus-mediated gene transfer, we attempted to gain insight into the functional significances of major growth factor receptor downstream cascades, Ras-extracellular signal-regulated kinase (Ras-ERK) pathway and phosphatidylinositol-3 kinase-Akt (PI3K-Akt) pathway. After neonatal hypoglossal nerve transection, the constitutively active Akt-overexpressing neurons could survive as well as those overexpressing Bcl-2, whereas the constitutively active ERK kinase (MEK)-overexpressing ones failed to survive. A dominant negative Akt experiment demonstrated that inhibition of Akt pathway hastened axotomy-induced neuronal death in the neonate. In addition, the dominant active Akt-overexpressing adult hypoglossal neurons showed accelerated axonal regeneration after axotomy. These results suggest that Akt plays dual roles in motoneuronal survival and nerve regeneration in vivo and that PI3K-Akt pathway is probably more vital in neuronal survival after injury than Ras-ERK pathway.

Key words: cell death; nerve injury; adenoviral gene transfer; hypoglossal; neuronal survival; nerve regeneration

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2082875-12$05.00/0

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