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

Abstract

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.

Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury

“…Of the neurotrophin receptors, p75 is the only receptor whose mRNA expression is dramatically induced in lesioned CSN, whereas Trk receptor expression remains unchanged (5,14). In agreement with in situ hybridization data (5), p75 protein was undetectable in the unlesioned cortex, but beginning 1 d after internal-capsule lesion, it was present in the lesioned cortex and reached highest levels by 3 d after lesion (Fig.…”

“…During embryonic development, neurotrophin 3 (NT3) promotes differentiation of cortical precursors into brainderived neurotrophic factor (BDNF)-dependent neurons in culture (12,13). When fully differentiated, these neurons adopt the adult phenotype and lose these trophic requirements (5,14). After axotomy at internal capsule levels, the survival of adult CSN is again regulated by endogenous neurotrophins, with BDNF supporting survival, whereas NT3 promotes death of BDNF-dependent CSN (5,14).…”

“…When fully differentiated, these neurons adopt the adult phenotype and lose these trophic requirements (5,14). After axotomy at internal capsule levels, the survival of adult CSN is again regulated by endogenous neurotrophins, with BDNF supporting survival, whereas NT3 promotes death of BDNF-dependent CSN (5,14). NT3, however, appears to act by means of an indirect mechanism and not by activating its own death program.…”

“…Furthermore, if proNGF binding to p75 is responsible for cell death after injury, disruption of the interaction between proNGF and p75 may be expected to prevent the death of cells that would otherwise undergo cell death in vivo. Here, these questions were addressed by using adult corticospinal neurons (CSN), for which p75 is implicated in death after axotomy (5).…”

Neurotrophins: Potential Therapeutic Tools for the Treatment of Spinal Cord Injury

“…Axotomy proximal to the cell body at the level of the internal capsule, however, results in a loss of approximately 50% of lesioned corticospinal motor neurons and atrophy of the surviving neurons [102]; this cell death and atrophy are completely prevented by high levels of BDNF or NT-3 treatment [23,102,103].…”