RT Journal Article
SR Electronic
T1 Endogenous Brain-Derived Neurotrophic Factor and Neurotrophin-3 Antagonistically Regulate Survival of Axotomized Corticospinal Neurons <em>In Vivo</em>
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3492
OP 3502
DO 10.1523/JNEUROSCI.21-10-03492.2001
VO 21
IS 10
A1 Klaus M. Giehl
A1 Stephan Röhrig
A1 Henk Bonatz
A1 Martin Gutjahr
A1 Britta Leiner
A1 Ilse Bartke
A1 Qiao Yan
A1 Louis F. Reichardt
A1 Carey Backus
A1 Andrew A. Welcher
A1 Kathrin Dethleffsen
A1 Pedro Mestres
A1 Michael Meyer
YR 2001
UL http://www.jneurosci.org/content/21/10/3492.abstract
AB 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 p75NTR 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 p75NTR 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 p75NTR 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.