Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2
No going back
The mammalian spinal cord coordinates neuronal systems across the body. Axons that cross the spinal cord midline during development first need permission to cross and then instruction not to keep crossing back and forth. Jaworski et al. studied the axonal guidance receptor ROBO3 and found a ligand NELL2 in mice that appears to help in this process.
Science, this issue p. 961
Abstract
Axon pathfinding is orchestrated by numerous guidance cues, including Slits and their Robo receptors, but it remains unclear how information from multiple cues is integrated or filtered. Robo3, a Robo family member, allows commissural axons to reach and cross the spinal cord midline by antagonizing Robo1/2–mediated repulsion from midline-expressed Slits and potentiating deleted in colorectal cancer (DCC)–mediated midline attraction to Netrin-1, but without binding either Slits or Netrins. We identified a secreted Robo3 ligand, neural epidermal growth factor-like-like 2 (NELL2), which repels mouse commissural axons through Robo3 and helps steer them to the midline. These findings identify NELL2 as an axon guidance cue and establish Robo3 as a multifunctional regulator of pathfinding that simultaneously mediates NELL2 repulsion, inhibits Slit repulsion, and facilitates Netrin attraction to achieve a common guidance purpose.
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Supplementary Material
Summary
Materials and Methods
Figs. S1 to S4
Table S1
Resources
File (jaworski-sm.pdf)
References and Notes
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Information & Authors
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Published In
Science
Volume 350 | Issue 6263
20 November 2015
20 November 2015
Copyright
Copyright © 2015, American Association for the Advancement of Science.
Submission history
Received: 17 August 2015
Accepted: 16 October 2015
Published in print: 20 November 2015
Acknowledgments
We thank the members of the Tessier-Lavigne laboratory for discussion and suggestions. We are grateful to C. Culiat for sharing NELL1 mutant mice, J. Ernst for help with purification of recombinant proteins, S. Warming for advice on the assembly of the NELL2 targeting vector by recombineering, M. Roose-Girma for help with generation of NELL2 mutant mice, and M. Yaylaoglu for providing probe templates for in situ hybridization. The NELL2 conditional and full knockout mice as well as cDNA constructs described here are available from A.J. under a material transfer agreement with Genentech. We also thank N. Velarde, D. Collado, K. Sono, and Y. Zhou for technical assistance. This work was supported by Genentech, The Rockefeller University, and Brown University. The supplementary materials contain additional data. Roche provided part of the support for the study but does not stand to benefit from it because no patents were filed.
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