New views on retinal axon development: a navigation guide

Abstract

The eye is a peripheral outpost of the central nervous system (CNS) where the retinal ganglion cells (RGCs) reside. RGC axons navigate to their targets in a remarkably stereotyped and error-free manner and it is this process of directed growth that underlies the complex organization of the adult brain. The RGCs are the only retinal neurons to project into the brain and their peripheral location makes them an unusually accessible population of projection neurons for experiments involving in vivo gene transfer, anatomical tracing, transplantation and in vitro culture. In this paper, we review recent findings that have contributed to our understanding of some of the guidance decisions that axons make in the developing visual system. We look at two choice points in the pathway, the optic nerve head (onh) and the midline chiasm, and discuss evidence that supports the idea that key molecules in guiding axon growth at these junctures are netrin-1 (onh) and ephrin-B (chiasm). In the optic tectum where RGC axon terminals are arrayed in topographic order, we present experimental evidence to suggest that in the dorso-ventral dimension, the B-type ephrins and Eph receptors are of prime importance, possibly through attractive interactions. This complements the anterior-posterior topographic mapping known to be mediated through A-type ephrin/Eph repulsive interactions. An emerging theme is that guidance molecules such as ephrin-B and netrin-1 have complex patterns of restricted expression in the pathway and play multiple and changing roles in axon guidance.

Fig. 1. Netrin-1 helps to guide the growth of axons out of the eye

(A) The arrangement of retinal ganglion cells (RGCs; red) along the vitreal surface of the retina (grey) where laminin is located. Axons grow across the vitreal surface and make a sharp bend at the entrance to the optic nerve head (ONH, dark blue; arrow at B) where netrin-1 is localized. (B) A growth cone entering the ONH where it encounters laminin and netrin-1 on the vitreal surface and netrin-1 only in the ONH. It is hypothesised that the laminin and netrin-1 signals combine to repel axons away from the surface and force axons into the netrin-1-rich ONH, and so out of the eye.

Fig. 2. Ephrin-B mediates divergent axon choice at the optic chiasm

(A) Shows the distribution of ephrin-B and EphB receptor in the embryonic retina (left two panels) and the chiasm of pre- and post- and metamorphic Xenopus (right two panels). Ephrin-B is expressed in a high-dorsal to low-ventral gradient in the retina while the EphB receptor is expressed in an opposing high-ventral to low-dorsal gradient. Ephrin-B is not expressed at the chiasm until metamorphosis which coincides with the initiation of the ipsilateral projection. A subpopulation of ventral EphB-expressing cells project ipsilaterally at metamorphosis. Photomicrographs adapted from Nakagawa et al., 2000 and Mann et al., 2002. (B) Model of repulsive axon guidance at the chiasm. See text for details. Diagram adapted from Mann and Holt, 2001.

Fig. 3. Topographic mapping along the dorso-ventral axis involves attractive ephrin/EphB interactions

(A) The normal distribution of B-type ephrins and receptors in the retina and tectum. Regions of high ephrin-B expression (dorsal retina) project to regions of high receptor expression (ventral tectum) indicative of matching, attractive interactions. (B) Inhibition of EphB receptor function in dorsal retina causes axons to map significantly further dorsally (like ventral cells) and ectopic expression of EphB in ventral RGCs causes them to map ventrally (like dorsal cells) instead of dorsally. Summary of data from Mann et al., 2002.

Fig. 4. Summary of distribution and role of netrin-1, A- and B-type ephrins and receptors in the developing visual pathway

Eye: dorsoventral axis is top to bottom, nasotemporal axis left to right. Tectum: mediolateral (mammals) and dorsoventral (frogs) is top to bottom, anterior-posterior axis is left to right.