Journal of Cell Science, Vol 113, Issue 7 1139-1148, Copyright © 2000 by Company of Biologists

JOURNAL ARTICLES

Unscheduled re-entry into the cell cycle induced by NGF precedes cell death in nascent retinal neurones

JM Frade
Instituto Cajal de Neurobiologia, CSIC, Avenida Doctor Arce 37, Madrid E28002, Spain. isrf303@fresno.csic.es.

During their early postmitotic life, a proportion of the nascent retinal ganglion cells (RGCs) are induced to die as a result of the interaction of nerve growth factor (NGF) with the neurotrophin receptor p75. To analyse the mechanisms by which NGF promotes apoptosis, an in vitro culture system consisting of dissociated E5 retinal cells was established. In this system, NGF-induced apoptosis was only observed in the presence of insulin and neurotrophin-3, conditions that favour the birth of RGCs and other neurones expressing the glycoprotein G4. The pro-apoptotic effect of NGF on the G4-positive neurones was evident after 10 hours in vitro and was preceded by a significant upregulation of cyclin B2, but not cyclin D1, and the presence of mitotic nuclei in these cells. Brain-derived neurotrophic factor prevented both the increase of cyclin B2 expression in the G4-positive neurones and the NGF-induced cell death. Finally, pharmacologically blocking cell-cycle progression using the cyclin-dependent kinase inhibitor roscovitine prevented NGF-induced cell death in a dose-dependent manner. These results strongly suggest that the apoptotic signalling initiated by NGF requires a driving stimulus manifested by the neuronal birth and is preceded by the unscheduled re-entry of postmitotic neurones into the cell cycle.

This article has been cited by other articles:

				B. Srinivasan, C. H. Roque, B. L. Hempstead, M. R. Al-Ubaidi, and R. S. Roque Microglia-derived Pronerve Growth Factor Promotes Photoreceptor Cell Death via p75 Neurotrophin Receptor J. Biol. Chem., October 1, 2004; 279(40): 41839 - 41845. [Abstract] [Full Text] [PDF]

				P. M. Price, R. L. Safirstein, and J. Megyesi Protection of renal cells from cisplatin toxicity by cell cycle inhibitors Am J Physiol Renal Physiol, February 1, 2004; 286(2): F378 - F384. [Abstract] [Full Text] [PDF]

				L. M. Frago, S. Canon, E. J. de la Rosa, Y. Leon, and I. Varela-Nieto Programmed cell death in the developing inner ear is balanced by nerve growth factor and insulin-like growth factor I J. Cell Sci., February 1, 2003; 116(3): 475 - 486. [Abstract] [Full Text] [PDF]

				L. M. Schang Cyclin-dependent kinases as cellular targets for antiviral drugs J. Antimicrob. Chemother., December 1, 2002; 50(6): 779 - 792. [Abstract] [Full Text] [PDF]

				M Gonzalez-Hoyuela, J. Barbas, and A Rodriguez-Tebar The autoregulation of retinal ganglion cell number Development, January 1, 2001; 128(1): 117 - 124. [Abstract] [PDF]

				P. P. Roux, A. L. Bhakar, T. E. Kennedy, and P. A. Barker The p75 Neurotrophin Receptor Activates Akt (Protein Kinase B) through a Phosphatidylinositol 3-Kinase-dependent Pathway J. Biol. Chem., June 15, 2001; 276(25): 23097 - 23104. [Abstract] [Full Text] [PDF]