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A relative signalling model for the formation of a topographic neural map

Nature volume 431, pages 847–853 (2004)Cite this article

Abstract

The highly ordered wiring of retinal ganglion cell (RGC) neurons in the eye to their synaptic targets in the superior colliculus of the midbrain has long served as the dominant experimental system for the analysis of topographic neural maps1,2,3. Here we describe a quantitative model for the development of one arm of this map—the wiring of the nasal–temporal axis of the retina to the caudal–rostral axis of the superior colliculus. The model is based on RGC–RGC competition that is governed by comparisons of EphA receptor signalling intensity, which are made using ratios of, rather than absolute differences in, EphA signalling between RGCs4. Molecular genetic experiments, exploiting a combinatorial series of EphA receptor knock-in and knockout mice, confirm the salient predictions of the model, and show that it both describes and predicts topographic mapping.

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Figure 1: EphA mRNAs in the retina.
Figure 2: EphA expression in the knock-ins.
Figure 3: Map perturbation in Isl2-EphA3ki/+EphA4+/- mice.
Figure 4: Rlrs functions and measured retinocollicular maps in all possible Isl2-EphA3/EphA4 compound genotypes.
Figure 5: RS derivation of the wild-type map.

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Acknowledgements

We thank C. F. Stevens for mathematical insights; M. Dottori and S. Pfaff for the EphA4 mutants and Isl2-τlacZ mice, respectively; D. O'Leary, T. McLaughlin and R. Hindges for discussions and advice on DiI injections; T. Jessell, C. Kintner, M. Meister, S. Pfaff and L. Wolpert for comments on the manuscript; and J. Hash for excellent technical assistance. This work was supported by grants from the NIH (G.L.), the Philippe Foundation (M.R.), and the Bettencourt–Schueller Foundation (M.R.). M.R. was a fellow from Fondation pour la Recherche Medicale.

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  1. Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California, 92037, USA

    Michaël Reber, Patrick Burrola & Greg Lemke

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  1. Michaël Reber
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Correspondence to Greg Lemke.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1 and Discussion

This supplement elaborates on equations describing the EphA and ephrin-A gradients in the mouse, and discusses the assumption of EphA receptor interchangeability. (PDF 148 kb)

Supplementary Figure 2 and Discussion

This supplement describes the direct visualization of EphA3+ axons in heterozygous knock-ins using Isl2-tlacZ as an axonal marker, and its use in multiple compound mutant backgrounds. (PDF 5616 kb)

Supplementary Figure 3 and Discussion

This supplement describes a speculative model for how ensemble-wide ratiometric ∑EphA comparisons may be translated into biased competition for BDNF during axonal competition and map formation in the SC. (PDF 1200 kb)

Supplementary Discussion

This supplement discusses retinal expression of ephrin-As, and the implications of results described in the text for their hypothesized roles in retinocollicular mapping. (PDF 64 kb)

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Reber, M., Burrola, P. & Lemke, G. A relative signalling model for the formation of a topographic neural map. Nature 431, 847–853 (2004). https://doi.org/10.1038/nature02957

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