QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, January 28, 2009, 29(4):1093-1104; doi:10.1523/JNEUROSCI.4103-08.2009

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Codeluppi, S. Articles by Pasquale, E. B. Search for Related Content PubMed PubMed Citation Articles by Codeluppi, S. Articles by Pasquale, E. B.

 Previous Article  |  Next Article 

Development/Plasticity/Repair
The Rheb–mTOR Pathway Is Upregulated in Reactive Astrocytes of the Injured Spinal Cord

Simone Codeluppi,^1,2 Camilla I. Svensson,³ Michael P. Hefferan,³ Fatima Valencia,¹ Morgan D. Silldorff,¹ Masakatsu Oshiro,^3,5 Martin Marsala,^3,4 and Elena B. Pasquale^1,2

¹Burnham Institute for Medical Research, La Jolla, California 92037, Departments of ²Pathology and ³Anesthesiology, University of California, San Diego, La Jolla, California 92093, ⁴Institute of Neurobiology, Slovak Academy of Sciences, 4 040 01 Koice, Slovakia, and ⁵Department of Anesthesiology, University of the Ryukyus, Okinawa 903-0213, Japan

Correspondence should be addressed to Elena B. Pasquale, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Email: elenap{at}burnham.org

Astrocytes in the CNS respond to tissue damage by becoming reactive. They migrate, undergo hypertrophy, and form a glial scar that inhibits axon regeneration. Therefore, limiting astrocytic responses represents a potential therapeutic strategy to improve functional recovery. It was recently shown that the epidermal growth factor (EGF) receptor is upregulated in astrocytes after injury and promotes their transformation into reactive astrocytes. Furthermore, EGF receptor inhibitors were shown to enhance axon regeneration in the injured optic nerve and promote recovery after spinal cord injury. However, the signaling pathways involved were not elucidated. Here we show that in cultures of adult spinal cord astrocytes EGF activates the mTOR pathway, a key regulator of astrocyte physiology. This occurs through Akt-mediated phosphorylation of the GTPase-activating protein Tuberin, which inhibits Tuberin's ability to inactivate the small GTPase Rheb. Indeed, we found that Rheb is required for EGF-dependent mTOR activation in spinal cord astrocytes, whereas the Ras–MAP kinase pathway does not appear to be involved. Moreover, astrocyte growth and EGF-dependent chemoattraction were inhibited by the mTOR-selective drug rapamycin. We also detected elevated levels of activated EGF receptor and mTOR signaling in reactive astrocytes in vivo in an ischemic model of spinal cord injury. Furthermore, increased Rheb expression likely contributes to mTOR activation in the injured spinal cord. Interestingly, injured rats treated with rapamycin showed reduced signs of reactive gliosis, suggesting that rapamycin could be used to harness astrocytic responses in the damaged nervous system to promote an environment more permissive to axon regeneration.

Key words: Akt; Tuberin; cell migration; rapamycin; ischemia; spinal cord injury

---

Received Aug. 27, 2008; revised Dec. 17, 2008; accepted Dec. 26, 2008.

Correspondence should be addressed to Elena B. Pasquale, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Email: elenap{at}burnham.org

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help