Increasing the specificity of neurotrophic factors

Abstract

Neurotrophic factors are capable of accomplishing many tasks. In addition to regulating neural cell survival and differentiation, they can influence changes in synaptic transmission and higher order behaviors, such as aggression, addiction, depression, learning, and memory. Because many trophic factors use receptor tyrosine kinases as a means for initiating signaling, a major question is how tyrosine phosphorylation events that lead to canonical MAP kinase, Akt, and phospholipase C-γ activities can account for so many diverse outcomes (1). The article in PNAS by Schalm et al. (2) on protocadherins and the glial-derived neurotrophic factor (GDNF) provides a unique insight into this question. GDNF is an important protein that was discovered in 1993 as a potent survival factor for midbrain dopaminergic neurons (3). It has been frequently touted as a treatment for Parkinson's disease. GDNF also exerts trophic effects on sympathetic, sensory, parasympathetic, and enteric neurons. The effects of GDNF and the related family members neurturin, artemin, and persephin are mediated by RET, a transmembrane receptor tyrosine kinase. GDNF ligands do not bind directly to RET but require GPI-anchored coreceptors [called GDNF receptor-α1–4] to activate the RET receptor, which efficiently increases intracellular ERK and PI3K activities and Ca2+ levels (4, 5). Many biological functions are affected by these ligand-receptor events, including proliferation and migration of progenitor cells, axon guidance, and chemoattraction (5). GDNF is also involved in synapse formation and neuronal excitability in possessing the ability to modulate postsynaptic … 1E-mail: moses.chao{at}med.nyu.edu.