NGF-Dependent Retrograde Signaling: Survival Versus Death

NGF-dependent retrograde signaling: survival versus death

Yang Zhou1, Ting-Jia Lu1, Zhi-Qi Xiong1

1Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031, China Cell Research (2009) 19:525-526. doi: 10.1038/cr.2009.47; published online 4 May 2009

Nerve growth factor (NGF) was which could also provide as the ret- nisms underlying NGF-dependent first discovered more than 5 decades rograde signals [7]. These hypotheses retrograde signaling. Previous studies ago as a molecule that promotes the are not mutually exclusive, and mul- from Campenot’s laboratory demon- survival and maturation of develop- tiple retrograde signals may exist. strated that NGF applied to distal ax- ing neurons in the peripheral nervous In this issue, Mok and colleagues ons of sympathetic neurons supports system [1]. NGF released from target describe a fundamentally different neuronal survival without transport of cells activates tropomyosin-related retrograde mechanism in which NGF NGF towards the cell bodies or TrkA kinase A (TrkA) on axon terminals and suppresses an apoptotic signal in distal phosphorylation in the cell bodies, triggers activation of PI3K/Akt, MEK/ axons [8]. Campenot’s group devel- suggesting that NGF binding to TrkA ERK, and PLCg signaling pathways. oped compartmentalized cultures of in distal axons triggers its downstream The signal then travels retrogradely sympathetic neurons which could seg- signaling cascades locally; afterwards along axon to cell body to promote regate the distal axons from cell bod- the signals travel retrogradely to the neuronal survival [2]. However, the ies and proximal axons by a distance cell bodies and communicate with nature of the retrograde signal remains of about 1 mm. By employing this soma [9]. In the current study, the au- mysterious. system with advantages of segregating thors found that neutralizing NGF in Several distinct types of retrograde cellular compartments, researchers distal segment of axons but not in the signals could derive from axon ter- could dissect the molecular mecha- cell bodies led to activation of c-jun minals [3]. First, NGF itself could undergo retrograde transport from terminals to cell body thus activates NGF intracellular TrkA receptor. Indeed, A 125 I-labeled NGF applied to axon p-GSK3 p-CREB pro-survival axon terminals in vivo was found to be ret- p-Akt rogradely transported to the neuronal cell bodies [4]. Second, NGF triggers TrkA endocytosis through binding to B TrkA, and the endocytic TrkA might GSK3 serve as the retrograde signal [5]. In p-c-jun pro-apoptotic axon supporting of this notion, both NGF caspase-3 and phosphorylated TrkA are found in endosomes [6]. Finally, NGF activates Figure 1 Schematic model of NGF-dependent sympathetic neuron survival or TrkA downstream signal molecules, apoptosis. (A) In the presence of NGF in axon terminals, retrogradely transmit- ted pro-survival signal facilitates neuronal survival via p-GSK3, p-Akt and p- CREB signaling pathways. (B) In the absence of NGF in axon terminals, retrograde pro-apoptotic signal leads to cleavage of caspase-3, dephosphorylation Correspondence: Zhi-Qi Xiong of GSK3, as well as phosphorylation of c-jun, thus promoting the apoptosis of E-mail: [email protected] sympathetic neuron. npg 526 and cleavage of caspase-3 in the cell Growing evidence suggests that notion be applied to situations such as bodies as illustrated in the Figure 1 of NGF supports neuronal survival by in nerve injury? Finding answers to schematic model. Interestingly, when activating TrkA and its downstream these questions is of high importance, NGF was applied to cell bodies while signals at the axon terminals which both for basic neurobiology and neu- deprived from the distal axons at the retrogradely transmit to the cell bod- rodegenerative diseases. same time, nuclear accumulation of ies. The current study demonstrates phosphorylated c-jun was still ob- that NGF deprivation at the distal References served, similar to cultures completely axons induces a transportable retro- deprived of NGF. These findings are grade pro-apoptotic signal traveling 1 Levi-Montalcini R, Angeletti PU. consistent with the notion that loss towards the cell bodies to initiate Nerve growth factor. Physiol Rev 1968; of NGF in the distal axons gener- apoptosis. Whether the inhibition of 48:534-569. 2 Zweifel LS, Kuruvilla R, Ginty DD. ates an apoptotic signal in the axon the retrograde apoptotic signal initi- Functions and mechanisms of retrograde terminals which travels to the cell ated at the axon terminals accounts for neurotrophin signalling. Nat Rev Neuro- bodies and activates c-jun. However, NGF-dependent neuronal survival or sci 2005; 6:615-625. local delivery of NGF at cell bodies this novel mechanism operates along 3 Howe CL, Mobley WC. Long-distance protected against cell death despite with other distinct pathways within retrograde neurotrophic signaling. Curr the activation of c-jun, suggesting that the same neurons remains unknown. It Opin Neurobiol 2005; 15:40-48. survival signals activated by NGF in is possible that sustained pro-survival 4 Campenot RB, MacInnis BL. Retro- the cell bodies do not simply override signal is activated in the presence of grade transport of neurotrophins: fact and function. J Neurobiol 2004; 58:217- the retrograde apoptotic signal but NGF in axon terminals to antagonize 229. promote neuronal survival probably endogenous pro-apoptotic signal. 5 Ginty DD, Segal RA. Retrograde by acting downstream of c-jun. The Taken together, this study provides neurotrophin signaling: Trk-ing along axon-specific pro-apoptotic signal evidence in cultured sympathetic neu- the axon. Curr Opin Neurobiol 2002; was blocked by treating cultures with rons that deprivation of NGF at axon 12:268-274. the protein kinase C (PKC) inhibitor terminal triggers the pro-apoptotic 6 Ye H, Kuruvilla R, Zweifel LS, et rottlerin, but not by down-regulating signal which in turn transmits to cell al. Evidence in support of signaling d endosome-based retrograde survival the proposed isoform of PKC. This body. Results of this study also shed of sympathetic neurons. Neuron 2003; inconsistency between pharmacologi- lights on neurodegenerative diseases 39:57-68. cal approach and molecular manipula- [10]. However, several important is- 7 Miller FD, Kaplan DR. On Trk for tion may be due to the inefficiency of sues remain to be solved: how does retrograde signaling. Neuron 2001; siRNA knockdown or non-specific the retrograde signal transport from 32:767-770. effects of pharmacological inhibitor. axon terminal to cell body? Is it in a 8 Mok SA, Lund K, Campenot RB. A Further efforts to understand how cargo-like transport manner or a flow retrograde apoptotic signal originating in NGF-deprived distal axons of rat rottlerin exerts its protective effect of continuously signaling activation sympathetic neurons in compartmented showed that NGF deprivation in along the axon segment from distal cultures. Cell Research 2009; 19:xx- axon terminals activated GSK3 in a part to soma? What is the minimal xx. rottlerin-sensitive manner in the distal amount of NGF required to antago- 9 MacInnis BL, Campenot RB. Retrograde axons. Furthermore, inhibiting GSK3 nize the apoptotic signal? What is the support of neuronal survival without ret- activity in distal axons or cell bodies/ molecular mechanism underlying the rograde transport of nerve growth factor. proximal axons was able to prevent cross-talk between pro-survival and Science 2002; 295:1536-1539. NGF deprivation-induced apoptosis. pro-apoptotic signals? Does neurotro- 10 Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuro- However, how PKC and GSK3 were phin deprivation induce retrograde protection, and neural repair. Annu Rev activated at axon terminals were not pro-apoptotic signaling in sympa- Neurosci 2001; 24:1217-1281. clear. thetic neurons in vivo? Can the same

Cell Research | Vol 19 No 5 | May 2009