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  • Review Article
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Functions and mechanisms of retrograde neurotrophin signalling

Nature Reviews Neuroscience volume 6, pages 615–625 (2005)Cite this article

Key Points

  • Limiting amounts of neurotrophins and other neurotrophic growth factors are expressed in target fields. Much of what we know about the functions of target-derived neurotrophic growth factors comes from studies of neurotrophins and the PNS. In the PNS, members of the neurotrophin family signal retrogradely, often across long distances, to support neuronal survival, thereby sculpting connectivity.

  • Target-derived growth factors signal locally, within distal axons, and retrogradely to regulate neuronal specification, axonal extension and branching, elaboration of dendrites, neurotransmitter phenotype, synaptogensis and synaptic function.

  • Considerable evidence from several laboratories supports the view that 'signalling endosomes' that contain both ligand and receptor are essential carriers of retrograde neurotrophin signals. Although there are likely to be other modes of retrograde signalling, their mechanisms have yet to be defined.

  • Growth factors use distinct mechanisms for ligand-dependent receptor internalization and trafficking. There is evidence for both clathrin-dependent and clathrin-independent modes of neurotrophin–tyrosine receptor kinase (Trk receptor) internalization.

  • Although some key events in the formation, sorting and trafficking of the signalling endosome are becoming clearer, the determination of the biochemical composition of this signalling endosome will give us a more complete understanding of retrograde signalling.

  • At present, challenges in the field include establishing the molecular composition of the signalling endosome, defining other modes of retrograde signalling and determining whether defective retrograde trophic factor signalling contributes to neurodegenerative disorders.

Abstract

Neuronal connections are established and refined through a series of developmental programs that involve axon and dendrite specification, process growth, target innervation, cell death and synaptogenesis. Many of these developmental events are regulated by target-derived neurotrophins and their receptors, which signal retrogradely over long distances from distal-most axons to neuronal cell bodies. Recent work has established many of the cellular and molecular events that underlie retrograde signalling and the importance of these events for both development and maintenance of proper neural connectivity.

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Figure 1: Compartmentalized neuronal cell culture system.
Figure 2: Retrograde neurotrophin signalling instructs various developmental programs.
Figure 3: Neurotrophins and their receptors use various modes of internalization.
Figure 4: The signalling endosome.

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Acknowledgements

We thank C. Deppmann, N. Glebova and K. Scangos for comments on the manuscript. The authors' work is supported by a National Institutes of Health grant. D.G.G. is an investigator of the Howard Hughes Medical Institute.

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  1. Department of Neuroscience, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, 21205-2185, Maryland, USA

    Larry S. Zweifel & David D. Ginty

  2. Department of Biology, The Johns Hopkins University Zanvyl Krieger School of Arts and Sciences, Baltimore, 21218, Maryland, USA

    Rejji Kuruvilla

Authors
  1. Larry S. Zweifel
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  2. Rejji Kuruvilla
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  3. David D. Ginty
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Correspondence to David D. Ginty.

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DATABASES

Entrez Gene

Akt

ATF2

Bax

Bcl2

BDNF

CGRP

CNTF

CREB

EEA1

ERK1

ERK2

EGF

FRS2

GDNF

LIF

NGF

NT3

NT4

PEA3

PI3K

PLCγ

p75NTR

Shc

TrkA

TrkB

TrkC

Glossary

PRONEUROTROPHINS

Uncleaved forms of the neurotrophins that bind with high affinity to p75NTR.

BAX

Pro-apoptotic BCL2 family member. BAX translocation from the cytosol to the mitochondria facilitates cytochrome c release.

APOPTOSOME

Heteromeric protein complex containing cytochrome c, APAF-1 and procaspase-9. Triggers a cascade of caspase activation and proteolysis.

Ras, Rap

Small GTPases that are involved in growth, differentiation and cellular signalling. They require the binding of GTP to enter into their active state.

MITOGEN-ACTIVATED PROTEIN KINASE SIGNALLING

A signalling cascade that relays signals from the plasma membrane to the nucleus. Mitogen-activated protein kinases (MAPKs), which represent the last step in the pathway, are activated by a wide range of proliferation- or differentiation-inducing signals. ERKs are among the best-characterized MAPKs.

SH2 AND PTB DOMAINS

Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains bind directly to canonical sites of tyrosine phosphorylation (pYXN and NPXpY, respectively, where p represents phosphorylation) that are found in many tyrosine kinases. These domains are commonly found in adaptor proteins such as Shc and FRS2. For the Trk receptors, Shc and FRS2 bind to Y-490.

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Zweifel, L., Kuruvilla, R. & Ginty, D. Functions and mechanisms of retrograde neurotrophin signalling. Nat Rev Neurosci 6, 615–625 (2005). https://doi.org/10.1038/nrn1727

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