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Semaphorin 7A promotes axon outgrowth through integrins and MAPKs

Abstract

Striking parallels exist between immune and nervous system cellular signalling mechanisms. Molecules originally shown to be critical for immune responses also serve neuronal functions, and similarly neural guidance cues can modulate immune function. We show here that semaphorin 7A (Sema7A), a membrane-anchored member of the semaphorin family of guidance proteins previously known for its immunomodulatory effects, can also mediate neuronal functions. Unlike many other semaphorins, which act as repulsive guidance cues, Sema7A enhances central and peripheral axon growth and is required for proper axon tract formation during embryonic development. Unexpectedly, Sema7A enhancement of axon outgrowth requires integrin receptors and activation of MAPK signalling pathways. These findings define a previously unknown biological function for semaphorins, identify an unexpected role for integrins and integrin-dependent intracellular signalling in mediating semaphorin responses, and provide a framework for understanding and interfering with Sema7A function in both immune and nervous systems.

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Figure 1: Sema7A promotes growth of central and peripheral axons.
Figure 2: Sema7A stimulates lateral olfactory tract (LOT) formation.
Figure 3: LOT formation is defective in Sema7A homozygous mutant mice.
Figure 4: Integrins mediate Sema7A signalling.
Figure 5: Integrin-induced MAPK signalling is necessary for Sema7A-mediated axon growth.

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Acknowledgements

We thank A. Ghosh, D. D. Ginty and J. T. Yang for comments on the manuscript; Y. Wu for excellent technical assistance; the Johns Hopkins Transgenic Core Facility for blastocyst injections and discussions; members of the Kolodkin, Ginty and Ghosh laboratories, and L. Tamagnone and Z. He for helpful discussions; J. F. Cloutier for help with the VNE cultures; R. Kuruvilla for help with the MAPK/FAK experiments; K. Takamiya, R. Huganir, L. H. Rome, M. Tessier-Lavigne, Y. Luo, C.-M. Fan, A. Yamada, B. Lonze and R. J. Giger for constructs and cells. This work was supported by grants from the Netherlands Organization for Scientific Research and Human Frontier Science Program (to R.J.P), and The Kirsch Foundation and NIH/NINDS (to A.L.K.).

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Correspondence to Alex L. Kolodkin.

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R.J.P. and A.L.K. declare that they have no competing financial interests. J.J.P. and M.K.S. are shareholders in Amgen Corporation.

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Jeroen Pasterkamp, R., Peschon, J., Spriggs, M. et al. Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 424, 398–405 (2003). https://doi.org/10.1038/nature01790

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