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Published online 27 August 2001. doi:10.1083/jcb.200101068
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© The Rockefeller University Press, 0021-9525/2001/9/995 $5.00
The Journal of Cell Biology, Volume 154, Number 5, September 3, 2001 995-1006

Article

 Role of PI 3-kinase, Akt and Bcl-2–related proteins in sustaining the survival of neurotrophic factor–independent adult sympathetic neurons

Nina Orike1, Gayle Middleton2, Emma Borthwick2, Vladimir Buchman2, Timothy Cowen1 and Alun M. Davies2

1 Department of Anatomy and Developmental Biology, Royal Free Hospital School of Medicine, London NW3 2PF, United Kingdom
2 Department of Preclinical Veterinary Sciences, Royal (Dick) School of Veterinary Studies, Edinburgh, EH9 1QH, United Kingdom

Address correspondence to Alun Davies, Department of Preclinical Veterinary Sciences, Royal (Dick) School of Veterinary Studies, Summerhall Square, Edinburgh, EH9 1QH United Kingdom. Tel.: 44-131-650-6116. Fax: 44-131-650-7962. E-mail alun.davies{at}ed.ac.uk

By adulthood, sympathetic neurons have lost dependence on NGF and NT-3 and are able to survive in culture without added neurotrophic factors. To understand the molecular mechanisms that sustain adult neurons, we established low density, glial cell-free cultures of 12-wk rat superior cervical ganglion neurons and manipulated the function and/or expression of key proteins implicated in regulating cell survival. Pharmacological inhibition of PI 3-kinase with LY294002 or Wortmannin killed these neurons, as did dominant-negative Class IA PI 3-kinase, overexpression of Rukl (a natural inhibitor of Class IA PI 3-kinase), and dominant-negative Akt/PKB (a downstream effector of PI 3-kinase). Phospho-Akt was detectable in adult sympathetic neurons grown without neurotrophic factors and this was lost upon PI 3-kinase inhibition. The neurons died by a caspase-dependent mechanism after inhibition of PI 3-kinase, and were also killed by antisense Bcl-xL and antisense Bcl-2 or by overexpression of Bcl-xS, Bad, and Bax. These results demonstrate that PI 3-kinase/Akt signaling and the expression of antiapoptotic members of the Bcl-2 family are required to sustain the survival of adult sympathetic neurons.

Key Words: phosphoinositide 3-kinase; Akt kinase/protein kinase B; Bax; BcL-xL; signaling


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