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The Journal of Neuroscience, May 15, 2001, 21(10):3492-3502

Endogenous Brain-Derived Neurotrophic Factor and Neurotrophin-3 Antagonistically Regulate Survival of Axotomized Corticospinal Neurons In Vivo

Klaus M. Giehl¹, Stephan Röhrig¹, Henk Bonatz¹, Martin Gutjahr¹, Britta Leiner¹, Ilse Bartke², Qiao Yan³, Louis F. Reichardt⁴, Carey Backus⁴, Andrew A. Welcher³, Kathrin Dethleffsen⁵, Pedro Mestres¹, and Michael Meyer⁵

¹ University of Saarland, Department of Anatomy, 66421 Homburg/Saar, Germany, ² Pharma Research Penzberg, Roche Diagnostics GmbH, Department of Cell Biology, 82372 Penzberg, Germany, ³ Amgen, Thousand Oaks, California 91320-1799, ⁴ Department of Physiology and Howard Hughes Medical Institute, University of California, San Francisco, California 94143, and ⁵ Max-Planck-Institue of Neurobiology, 82152 Martinsried, Germany

Neuronal growth factors regulate the survival of neurons by their survival and death-promoting activity on distinct populations of neurons. The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) promote neuronal survival via tyrosine kinase (Trk) receptors, whereas NGF and BDNF can also induce apoptosis in developing neurons through p75^NTR receptors in the absence of their respective Trk receptors. Using mutant mice and inactivation of neurotrophins and their receptors with antibodies in rats, we show that endogenous NT-3 induces death of adult BDNF-dependent, axotomized corticospinal neurons (CSNs). When NT-3 is neutralized, the neurons survive even without BDNF, suggesting complete antagonism. Whereas virtually all unlesioned and axotomized CSNs express both trkB and trkC mRNA, p75 is barely detectable in unlesioned CSNs but strongly upregulated in axotomized CSNs by day 3 after lesion, the time point when cell death occurs. Blocking either cortical TrkC or p75^NTR receptors alone prevents death, indicating that the opposing actions of NT-3 and BDNF require their respective Trk receptors, but induction of death depends on p75^NTR cosignaling. The results show that neuronal survival can be regulated antagonistically by neurotrophins and that neurotrophins can induce neuronal death in the adult mammalian CNS. We further present evidence that signaling of tyrosine kinase receptors of the trk family can be crucially involved in the promotion of neuronal death in vivo.

Key words: neuronal death; neurotrophins; TrkC; p75; cortex; lesion

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21103492-11$05.00/0

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