Ephrin signaling in axon guidance

doi:10.1016/j.pnpbp.2004.05.025

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 28, Issue 5, August 2004, Pages 813-818

https://doi.org/10.1016/j.pnpbp.2004.05.025 Get rights and content

Abstract

The multiple functions of a neuron depend on the proper assembly of axonal connections during the development of the nervous systems. This assembly involves the motile behavior of growth cones at the ends of elongating axons. The growth cones express receptors that bind to specific guidance molecules in the local environment. In turn, this initiates the attractive and repulsive forces required to give the appropriate direction to the elongating axon. The process implicates a tightly regulated remodeling of the actin cytoskeleton in response to the activation of the Rho GTPases, Cdc42, Rac and RhoA. In this article, we will review how the ephrin–Eph receptor system regulates the activity of the Rho GTPases, to modulate the mechanics of growth cone activity and then axon guidance.

Introduction

The correct organization of the nervous system requires that, during development, axons find their way to appropriate targets to establish the wiring and wiring connections that will support the sensory, motor and cognitive activities of life. Along the way, growth cones located at the leading edges of axons detect and sense environmental cues, the response to which guide the axons to their appropriate targets (Huber et al., 2003). Guidance molecules include contact-mediated or secreted molecules acting over short or long distances. Depending on spatiotemporal factors, individual guidance cues can function both as repellents and attractants. A prominent question is how growth cones sense and respond to guidance molecules. Recent studies have identified netrins, semaphorins, Slit and ephrins, as major axon guidance molecules (Dickson, 2002). Here, we will briefly review the mechanisms by which ephrins regulate axon guidance.

Section snippets

Ephrins and Eph receptors

Eph receptors are members of the tyrosine kinase receptors. They are involved in outside-in signaling that originates from themselves (forward signaling) or from their plasma-membrane-bound ephrin ligands (reverse signaling). During cell–cell communication, Ephs and ephrins also control the output signal that emanates from inside the cells (inside-out signaling). Ephrins are grouped in two classes: ephrin-As, which are anchored to the membrane by a glycosylphosphatidylinositol (GPI) and

Signaling through Ephrin and Eph receptors

The binding of ephrins to their Eph receptors induces “forward signaling”, in the Eph expressing cells and reverse signaling in the Ephrin expressing cells especially those that express the ephrins of the B family. This implicates that both the ligand and the receptor rearrange upon binding and adopt the active conformation that initiates signals into both interacting cells. The Eph receptors are activated following their binding to pre-clustered membrane attached ephrin ligands. Eph receptors

Structural composition of the growth cone

As mentioned above, growth cones are specialized and sensitive cytoskeletal motile structures located at the tips of developing axons Gallo and Letourneau, 2004, Zhou and Cohan, 2004. Their activity, in response to guidance cues, is the major determinant of axon guidance and elongation during development and it also contributes to axon regeneration after nerve injury. Growth cones are the most plastic area of the developing axon (Chan et al., 2003). Accordingly, their cytoskeleton differs from

Ephrins and Eph receptors in axon guidance in the visual system

Ephrins control axon guidance in several locations. For example, the ephrin–Eph system is critically involved in axon guidance at the midline where commissural axons cross to the contralateral side. At least three mechanisms of Eph–Ephrin action are involved, and they implicate both forward and reverse signaling. First, ephrin-B ligands expressed by midline cells are selective repellents for subsets of axons and prevent them from crossing the midline. Second, ephrin-B defines the position of

Future directions

Several questions remain open. In particular, a major challenge is to understand further the mechanisms by which the ephrin–Eph receptor systems regulate the functions of the nervous system in the adult. For example, the understanding of their role in axon regeneration might be crucial for treating patients suffering from nerve injuries and sectioning. In another context, the ephrin ligands–Eph receptors are critically involved in modulating angiogenesis. Here again, the understanding of the

Acknowledgements

The author would like to thank François Houle for drawing the figures.

This manuscript is dedicated to Corneille Radouco-Thomas who was my mentor and became my friend. With him, I wrote my first article that was published in Int. Z. Klin. Pharmakol. Ther. Toxikol. 3 (1971) 231–248. The title was “Pharmacomolecules–protein bioreceptor interactions”. This title was a little ahead of its time and it well characterized Dr. Radouco-Thomas, a creative man with a far vision on the future. Some 25 years

References (24)

P.A. Brittis et al.
Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target
Cell
(2002)
A. Brown et al.
Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling
Cell
(2000)
D.A. Feldheim et al.
Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping
Neuron
(2000)
R. Hindges et al.
EphB forward signaling controls directional branch extension and arborization required for dorsal-ventral retinotopic mapping
Neuron
(2002)
N. Lamarche et al.
Rac and Cdc42 induce actin polymerization and G1 cell cycle progression independently of p65PAK and the JNK/SAPK MAP kinase cascade
Cell
(1996)
Q. Lu et al.
Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction
Cell
(2001)
C.D. Nobes et al.
Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia
Cell
(1995)
S.M. Shamah et al.
EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin
Cell
(2001)
A.W. Boyd et al.
Signals from Eph and ephrin proteins: a developmental tool kit
Sci. STKE
(2001)
W.K. Chan et al.
Growth cones contain a dynamic population of neurofilament subunits
Cell Motil. Cytoskelet
(2003)

B.J. Dickson

Molecular mechanisms of axon guidance

Science

(2002)

G. Gallo et al.

Regulation of growth cone actin filaments by guidance cues

J. Neurobiol

(2004)

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Of note, IPA analysis showed that 78 mRNAs on the axonal guidance signaling pathway were validated or predicted to be targeted by all 5 DEMs (Fig. 2), suggesting axonal guidance cues may have been modified by sevoflurane exposure and axon growth status changed. In addition, several pathways contributing to regulating axonal guidance such as netrin signaling, slit signaling, ephrin signaling, semaphorin signaling, etc. (Bhat et al., 2007; Huot, 2004; Kim et al., 2017; Koncina et al., 2007; Nakamura et al., 2000; Xu and Henkemeyer, 2012; Zou et al., 2012) were regulated by the 5 DEMs. The specific effects of each miRNA on each individual target is difficult to distinguish using the present animal model, however, it is still reasonable to predict that axon growth during neural development is profoundly affected after sevoflurane exposure.
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Review articleEphrin signaling in axon guidance

Abstract

Introduction

Section snippets

Ephrins and Eph receptors

Signaling through Ephrin and Eph receptors

Structural composition of the growth cone

Ephrins and Eph receptors in axon guidance in the visual system

Future directions

Acknowledgements

Cell

Cell

Neuron

Neuron

Cell

Cell

Cell

Cell

Signals from Eph and ephrin proteins: a developmental tool kit

Sci. STKE

Growth cones contain a dynamic population of neurofilament subunits

Cell Motil. Cytoskelet

Molecular mechanisms of axon guidance

Science

Regulation of growth cone actin filaments by guidance cues

J. Neurobiol

Review article
Ephrin signaling in axon guidance