ReviewRetrograde neurotrophin signaling: Trk-ing along the axon
Introduction
Developing neurons depend on growth factors released by target fields for survival and ≥50% neurons die during development by a process called programmed cell death 1., 2.. What determines which neurons live or die? The neurotrophic hypothesis posits that target-derived survival factors are produced in limiting amounts, and that those neurons that successfully compete for these factors survive whereas less competitive neurons die. Substantial experimental support for the neurotrophic hypothesis exists, especially for neurons of the peripheral nervous system.
The best characterized target-derived growth factors, the neurotrophins, satisfy many predictions of the neurotrophic hypothesis. Neurotrophins — nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin 3 and 4 (NT3 and NT4) — are often made in limiting amounts by target tissues and the corresponding receptors — TrkA, B and C — are expressed by innervating neurons. Surgical removal of target tissue, or genetic ablation of target-derived factors, leads to death of innervating neurons. These data indicate that these target-derived factors are essential for survival of appropriately connected neurons during development. On the basis of a critical role for the neurotrophins, considerable attention has been directed towards elucidating their mechanism of action.
Our current understanding of the mechanisms of action of neurotrophins has emerged from studies in which cultured cells, such as rat pheochromocytoma-derived PC12 cells or primary neurons, were treated with neurotrophins to assess the intracellular signaling pathways that promote gene expression, neuronal survival, and process outgrowth (reviewed in [3]). In most such studies, the distance between the plasma membrane — the site where neurotrophins bind receptors — and the nucleus is but a few microns. Yet, in vivo, target-derived growth factors, such as NGF, normally bind to cell surface receptors on distal axons, which can be millimeters, centimeters or even one meter from the neuronal soma. Therefore, to appreciate fully neurotrophin signaling mechanisms in developing neurons, particular attention must be placed on unraveling the mysteries underlying long-range retrograde signaling from distal axons to neuronal cell bodies and nuclei. Recent studies, reviewed here, have focused on two spatial considerations of neurotrophin signaling in developing neurons. First, what is the nature of the retrograde neurotrophin signal and how is it propagated over remarkably long distances from distal axons to cell bodies? Second, do local specializations in neurotrophin signaling support spatially and functionally unique signals in developing neurons?
Section snippets
Trk receptors are retrograde signal carriers
Receptors for the neurotrophins are members of the Trk family of receptors and the structurally unrelated receptor p75. Recent experiments indicate that Trk receptors are primary retrograde signal carriers. In a sciatic nerve ligation model, activated phospho-Trk (P-Trk) receptors accumulate distal to a nerve ligation, in a manner dependent on endogenous NGF [4], strongly suggesting that they are retrogradely transported. Moreover, in vitro experiments employing compartmentalized cultures show
The signaling endosome model
How is the Trk signal conveyed from distal axons to cell bodies? Several models have been put forth to explain retrograde Trk signaling and prominent among these is the signaling endosome model (Fig. 1) [9]. In this model, target-derived neurotrophins bind Trk receptors at nerve terminals, and the neurotrophin–receptor complexes are then internalized by endocytosis. A fraction of endosomes [10••] evolve into specialized signaling vesicles that contain Trk receptors within the vesicle membranes
Alternative models for retrograde signaling
The enormous degree of complexity of growth factor signaling is important to bear in mind when considering mechanisms of retrograde signaling through a long axon. Current models of receptor tyrosine kinase signaling pathways include complex networks of relationships with extensive crosstalk. Similarly, there is unlikely to be a unitary mechanism for retrograde propagation of Trk signals; multiple retrograde signaling mechanisms are likely to coexist and interact.
One hypothesis is that
Location as a determinant of signaling specificity
An attractive feature of the signaling endosome model is that it provides a framework for understanding how stimuli acting either on distal axons or directly on cell bodies could evoke different cellular responses. Indeed, several lines of evidence support the idea that the subcellular location of receptor activation determines the pattern of activated signaling molecules. In early studies of membrane-embedded growth factor receptors, it was assumed that a signaling complex assembles at the
Retrograde signaling and neuronal survival
What are the functions of the retrograde signaling pathways described above? In accord with the classic neurotrophic hypothesis, two retrograde pathways — PI3K and Erk5 — are implicated in neurotrophin-dependent neuronal survival. Following neurotrophin stimulation of distal axons, PI3K is activated locally and thereby contributes to neuronal survival [29••]. This PI3K-mediated survival may be partially due to its role in regulating the initiation of retrograde transport of both NGF and
Conclusions and future directions
Recent studies have identified some of the adaptations that allow neurotrophins to initiate signals that can be transmitted through long axons, thereby stimulating survival. Considerable evidence supports a model in which vesicular transport of neurotrophin–Trk complexes propagates a signal. Other, non-vesicular modes of retrograde signaling are likely to function in parallel to promote survival. The MAPK modules activated during retrograde signals are spatially segregated, with Erk1/2
Acknowledgements
Our studies are supported by grants from the National Institutes of Health (NS35148 to R Segal and NS34814 to D Ginty). D Ginty is an assistant investigator of the Howard Hughes Medical Institute. We thank Ian Hendry and Bob Campenot for sharing unpublished data. We also thank Christoph Karch, Rejji Kuruvilla, Fiona Watson and Haihong Ye for helpful comments on the manuscript.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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