NGF-dependent retrograde signaling: survival versus death

Abstract

Nerve growth factor (NGF) was first discovered more than 5 decades ago as a molecule that promotes the survival and maturation of developing neurons in the peripheral nervous system [1]. NGF released from target cells activates tropomyosin-related kinase A (TrkA) on axon terminals and triggers activation of PI3K/Akt, MEK/ ERK, and PLCg signaling pathways. The signal then travels retrogradely along axon to cell body to promote neuronal survival [2]. However, the nature of the retrograde signal remains mysterious. Several distinct types of retrograde signals could derive from axon terminals [3]. First, NGF itself could undergo retrograde transport from terminals to cell body thus activates intracellular TrkA receptor. Indeed, 125I-labeled NGF applied to axon terminals in vivo was found to be retrogradely transported to the neuronal cell bodies [4]. Second, NGF triggers TrkA endocytosis through binding to TrkA, and the endocytic TrkA might serve as the retrograde signal [5]. In supporting of this notion, both NGF and phosphorylated TrkA are found in endosomes [6]. Finally, NGF activates TrkA downstream signal molecules, which could also provide as the retrograde signals [7]. These hypotheses are not mutually exclusive, and multiple retrograde signals may exist. In this issue, Mok and colleagues describe a fundamentally different retrograde mechanism in which NGF suppresses an apoptotic signal in distal axons [8]. Campenot’s group developed compartmentalized cultures of sympathetic neurons which could segregate the distal axons from cell bodies and proximal axons by a distance of about 1 mm. By employing this system with advantages of segregating cellular compartments, researchers could dissect the molecular mechanisms underlying NGF-dependent retrograde signaling. Previous studies from Campenot’s laboratory demonstrated that NGF applied to distal axons of sympathetic neurons supports neuronal survival without transport of NGF towards the cell bodies or TrkA phosphorylation in the cell bodies, suggesting that NGF binding to TrkA in distal axons triggers its downstream signaling cascades locally; afterwards the signals travel retrogradely to the cell bodies and communicate with soma [9]. In the current study, the authors found that neutralizing NGF in distal segment of axons but not in the cell bodies led to activation of c-jun