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First published online 14 February 2007
doi: 10.1242/dev.02808
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1 Department of Neuroscience, University of Geneva Medical School, CH-1211
Geneva, Switzerland.
2 Department of Anesthesiology, Pharmacology and Intensive Care, University
Hospital of Geneva, Geneva, Switzerland.
3 Laboratoire de Génétique et Physiologie du Développement,
CNRS 9943, Parc Scientifique de Luminy, Case 907, F-13288 Marseille Cedex 9,
France.
* Author for correspondence (e-mail: jozsef.kiss{at}medecine.unige.ch)
Accepted 5 January 2007
In the mammalian brain, ongoing neurogenesis via the rostral migratory stream (RMS) maintains neuronal replacement in the olfactory bulb throughout life. Mechanisms that regulate the final number of new neurons in this system include proliferation, migration and apoptosis. Here we show that the polysialylated isoforms of the neural cell adhesion molecule (PSA-NCAM) act as a pro-survival molecule in immature newborn neurons. Confocal microscopic analysis revealed a threefold increase in TUNEL-positive cells in the subventricular zone (SVZ) and the RMS of transgenic animals lacking the gene encoding NCAM (NCAM-/-), as compared with wild types. The enhanced apoptotic cell death occurred specifically in the population of mCD24-positive newborn neurons, but not in GFAP-positive astrocytes. Using in vitro cultures of purified SVZ-derived neurons, we demonstrate that the loss or inactivation of PSA on NCAM, as well as the deletion of NCAM, lead to reduced survival in response to neurotrophins including BDNF and NGF. These changes in cell survival are accompanied by an upregulation of p75 neurotrophin receptor expression in vitro as well as in vivo. Furthermore, the negative effects of PSA-NCAM inactivation on cell survival could be prevented by the pharmacological blockade of the p75 receptor-signaling pathway. We propose that PSA-NCAM may promote survival by controlling the expression of the p75 receptor in developing neurons.
Key words: Neuronal survival, Neurotrophin, PSA-NCAM, p75 (Ngfr), Olfactory bulb, Neurogenesis
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