Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration.
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.
Namikawa
K
K
Department of Anatomy, Asahikawa Medical College, Asahikawa, Hokkaido, 078-8510 Japan.
Honma
M
M
Abe
K
K
Takeda
M
M
Mansur
K
K
Obata
T
T
Miwa
A
A
Okado
H
H
Kiyama
H
H
D000818:Animals; D000831:Animals, Newborn; D019771:Axotomy; D016923:Cell Death / Q000502:physiology*; D004789:Enzyme Activation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000502:physiology; D007002:Hypoglossal Nerve / Q000502:physiology; D061228:Hypoglossal Nerve Injuries; D009046:Motor Neurons / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats
D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494920:Akt1 protein, rat