Regulation of mRNA expression involved in Ras and PKA signal pathways during rat hypoglossal nerve regeneration

Kiryu, Sumiko; Morita, Nagayoshi; Ohno, Kohji; Maeno, Hiroshi; Kiyama, Hiroshi

doi:10.1016/0169-328x(94)00241-6

Cited by 41 publications

(19 citation statements)

References 37 publications

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“…This suggests the importance of Akt activation in response to nerve injury for survival. In contrast, expression of ERK1 mRNA, which is a pivotal kinase in Ras-ERK pathway, was transiently upregulated in both adult and neonate (Kiryu et al, 1995a;and K. Mansur, unpublished data). The transient upregulation of ERK alone in the neonate seems not to promote neuronal survival.…”

Section: Activation Of Akt In Response To Nerve Injurymentioning

confidence: 98%

“…In such gene screening studies, molecules restricted to certain intracellular signaling pathways were repeatedly hit. These are, for instance, Shc, 14-3-3, extracellular signalregulated kinase 1 (ERK1), ERK kinase 1 (MEK1), phosphatidylinositol-3 kinase (PI3K), and Akt (Kiryu et al, 1995a;Ito et al, 1996;Owada et al, 1997;Namikawa et al, 1998;Tanabe et al, 1998), which are molecules located downstream of growth factor receptor signaling pathways, in particular Ras-ERK and PI3K-Akt cascades (for review, see Kaplan and Miller, 1997). The in vitro studies using culture cells have also indicated that these two pathways are vital for neuronal survival (for review, see Pettmann and Henderson, 1998).…”

mentioning

confidence: 99%

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

Namikawa¹,

Honma

Abe³

et al. 2000

J. Neurosci.

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169

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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 signalregulated 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.

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Section: Activation Of Akt In Response To Nerve Injurymentioning

confidence: 98%

mentioning

confidence: 99%

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

Namikawa¹,

Honma

Abe³

et al. 2000

J. Neurosci.

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217

169

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“…For in situ hybridization, animals were decapitated and brains were removed and quickly frozen in powdered dry ice. In situ hybridization was performed as described previously (Kiryu et al, 1995).…”

Section: Methodsmentioning

confidence: 99%

Critical Role for DP5/Harakiri, a Bcl-2 Homology Domain 3-Only Bcl-2 Family Member, in Axotomy-Induced Neuronal Cell Death

Imaizumi¹,

Benito²,

Kiryu‐Seo³

et al. 2004

J. Neurosci.

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The survival of neurons is maintained primarily by neurotrophic factors that suppress the apoptotic program. Axotomy or removal of peripheral targets causes neuronal cell death, but the mechanisms involved in the induction of this type of cell death remain poorly understood. Here, we show that DP5/Harakiri, a Bcl-2 homology domain 3-only member of the Bcl-2 family, is induced in motoneurons after transection of the hypoglossal nerve in mice and in sympathetic neurons after nerve growth factor (NGF) withdrawal. To assess the role of DP5 in neuronal cell death, mutant mice deficient in DP5 were generated by gene targeting. DP5Ϫ/Ϫ mice were viable and exhibited normal postnatal development. Notably, motoneurons from DP5 Ϫ/Ϫ mice were highly protected from cell death induced by resection of the hypoglossal nerve compared with motoneurons from DP5 ϩ/ϩ littermate mice. In addition, deficiency of DP5 in superior cervical ganglia (SCG) neurons resulted in delayed neuronal cell death triggered by NGF withdrawal. Analysis of SCG neurons from DP5 Ϫ/Ϫ mice revealed increased preservation of mitochondrial membrane potential and reduced activation of caspase-3 compared with neurons from wild-type mice. These results indicate that DP5 plays an important role in neuronal cell death induced by axotomy and NGF deprivation through the regulation of mitochondrial function and caspase-3 activation.

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“…For the death signal p53-activated death pathways, BAX, BH3-only proteins, and caspases are activated (Morita et al, 1996;Kiryu-Seo et al, 2005). For the survival signal, a group of neurotrophic factor receptors, intracellular signaling molecules such as ERK, PI3K, and Akt, and free-radical scavengers are all activated (Kiryu et al, 1995b;Hirota et al, 1996;Yao et al, 1997;Mansur et al, 1998;Namikawa et al, 2000;Honma et al, 2002).…”

Section: Introductionmentioning

confidence: 98%

Suture of Transected Nerve Suppresses Expression of BH3-Only Protein Noxa in Nerve-Transected Motor Neurons of C57BL/6J Mouse

Gamo

Kiryu‐Seo

Yoshikawa

et al. 2007

Journal of Neurotrauma

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Disrupted peripheral nerves are typically sutured as spontaneous recovery does not always occur. However, the molecular mechanisms involved in nerve regeneration following end-to-end nerve suture are obscure. Here, we investigated effects of end-to-end nerve suture after peripheral nerve transection on motor neurons, using the C57BL/6J mouse hypoglossal nerve injury model. In this animal model, 60-80% of injured motor neurons gradually progress to neuronal death, while the remaining injured neurons survive and regenerate. Mice were divided into the Cut and Suture groups. In the Cut group, the right hypoglossal nerve was transected. In the Suture group, the right hypoglossal nerve was transected and then was repaired using end-to-end nerve suture. We assessed differences between the Cut and Suture groups by analyzing the neuronal survival rate by thionine staining and the nerve terminal regeneration rate by vesicular acetylcholine transporter (VAChT) immunohistochemistry, which is a marker for cholinergic presynaptic terminal. We found that 82.9% of motor neurons survived in the Suture group, whereas only 39.2% of motor neurons did in the Cut group 56 days after surgery. At that time point, 86% of presynaptic terminals compared to controls were regenerated in the Suture group, and 21% were regenerated in the Cut group. These results demonstrate that peripheral nerve suture prevented death of nerve-transected motor neurons and promoted nerve regeneration. We also examined expression profiles of major survival and death signal-associated genes in hypoglossal nuclei using in situ hybridization and real-time polymerase chain reaction (PCR). Although most of the survival- and death-associated genes were regulated in a similar manner in both groups, expression of BH3-only protein Noxa mRNA was significantly lower in the Suture than in the Cut group. A significant suppression of Noxa expression by the Suture may be a major reason why nerve suture induces survival and regeneration of nerve-injured motor neurons.

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Regulation of mRNA expression involved in Ras and PKA signal pathways during rat hypoglossal nerve regeneration

Cited by 41 publications

References 37 publications

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

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

Critical Role for DP5/Harakiri, a Bcl-2 Homology Domain 3-Only Bcl-2 Family Member, in Axotomy-Induced Neuronal Cell Death

Suture of Transected Nerve Suppresses Expression of BH3-Only Protein Noxa in Nerve-Transected Motor Neurons of C57BL/6J Mouse

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