Axons rely on guidance cues to reach remote targets during nervous system development1. A well-studied model system for axon guidance is the retinotectal projection. The retina can be divided into halves; the nasal half, next to the nose, and the temporal half. A subset of retinal axons, those from the temporal half, is guided by repulsive cues expressed in a graded fashion in the optic tectum2,3, part of the midbrain. Here we report the cloning and functional characterization of a membrane-associated glycoprotein, which we call RGM (repulsive guidance molecule). This molecule shares no sequence homology with known guidance cues, and its messenger RNA is distributed in a gradient with increasing concentration from the anterior to posterior pole of the embryonic tectum. Recombinant RGM at low nanomolar concentration induces collapse of temporal but not of nasal growth cones and guides temporal retinal axons in vitro, demonstrating its repulsive and axon-specific guiding activity.
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Yu, T. W. & Bargmann, C. I. Dynamic regulation of axon guidance. Nature Neurosci. 4, 1169–1176 (2001)
Walter, J. et al. Recognition of position-specific properties of tectal cell membranes by retinal axons in vitro. Development 101, 685–696 (1987)
Walter, J., Müller, B. & Bonhoeffer, F. Axonal guidance by an avoidance mechanism. J. Physiol. (Paris) 84, 104–110 (1990)
Cheng, H. J. et al. Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell 82, 371–381 (1995)
Drescher, U. et al. In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases. Cell 82, 359–370 (1995)
Stahl, B. et al. Biochemical characterization of a putative axonal guidance molecule of the chick visual system. Neuron 5, 735–743 (1990)
Kozak, M. An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 15, 8125–8148 (1987)
Kyte, J. & Doolittle, R. F. A simple method for displaying the hydropathic character of a protein. J. Mol. Biol. 157, 105–132 (1982)
Ruoslahti, E. RGD and other recognition sequences for integrins. Annu. Rev. Cell Dev. Biol. 12, 697–715 (1996)
Sadler, J. E. Biochemistry and genetics of von Willebrand factor. Annu. Rev. Biochem. 67, 395–424 (1998)
Rathjen, F. G. et al. Membrane glycoproteins involved in neurite fasciculation. J. Cell Biol. 104, 343–353 (1987)
Cox, E. C., Müller, B. & Bonhoeffer, F. Axonal guidance in the chick visual system: posterior tectal membranes induce collapse of growth cones from the temporal retina. Neuron 4, 31–37 (1990)
Baier, H. & Bonhoeffer, F. Axon guidance by gradients of a target-derived component. Science 255, 472–475 (1992)
Wilm, M. et al. Femtomole sequencing of proteins from polyacrylamide gels by nanoelectrospray mass spectrometry. Nature 379, 466–469 (1996)
We thank P. Sonderegger for providing an embryonic chicken cDNA library, F. Rathjen for antibodies, H. Pachowsky for technical help; and S. Arber and B. Fackler for comments and suggestions. This work was supported by the Sonderforschungsbereich (B.K.M.) and the Danish National Research Foundation (M.M.).
The authors declare that they have no competing financial interests.
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Monnier, P., Sierra, A., Macchi, P. et al. RGM is a repulsive guidance molecule for retinal axons. Nature 419, 392–395 (2002) doi:10.1038/nature01041
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