Recent advances in understanding context-dependent mechanisms controlling neurotrophin signaling and function.

Mark Bothwell

doi:10.12688/f1000research.19174.1

Abstract

Complex mechanisms control the signaling of neurotrophins through p75 NTR and Trk receptors, allowing cellular responses that are highly context dependent, particularly in the nervous system and particularly with regard to the neurotrophin brain-derived neurotrophic factor (BDNF). Recent reports describe a variety of sophisticated regulatory mechanisms that contribute to such functional flexibility. Mechanisms described include regulation of trafficking of alternative BDNF transcripts, regulation of post-translational processing and secretion of BDNF, engagement of co-receptors that influence localization and signaling of p75 NTR and Trk receptors, and control of trafficking of receptors in the endocytic pathway and during anterograde and retrograde axonal transport.

Highlights

Neurotrophins are a small orthologous family of growth factors, consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4) in mammals
Trk receptors are canonical receptor tyrosine kinases. p75NTR is a member of the tumor necrosis factor (TNF) receptor superfamily and the subclass of those receptors known as death receptors because they contain a cytoplasmic death domain that mediates key signaling effects[8]
In sympathetic neurons, an alternative mode of p75NTR signaling, leading to nuclear accumulation of NRIF and cell death, involves γ-secretase-mediated cytoplasmic release of the intracellular domain (ICD) of p75NTR, which is promoted by neurotrophindependent activation of Trk receptors but is not directly promoted by neurotrophin binding p75NTR38–40. p75NTR signaling alternatively can activate cell survival-promoting pathways, such as the NF-κB pathway, or cell death-inducing pathways, such as the Jun N-terminal kinase (JNK) pathway, and mechanisms determining these alternative responses are poorly understood

Summary

19 Sep 2019

Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions. The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Pontificia Universidad Católica de Chile, Santiago, Chile. Any comments on the article can be found at the end of the article

Introduction

Conclusions

Bothwell M