Abstract
The search to understand the mechanisms regulating brain wiring has relied on biochemical purification approaches in vertebrates and genetic approaches in invertebrates to identify molecular cues and receptors for axon guidance. Here we describe a phenotype-based gene-trap screen in mice designed for the large-scale identification of genes controlling the formation of the trillions of connections in the mammalian brain. The method incorporates an axonal marker, which helps to identify cell-autonomous mechanisms in axon guidance, and has generated a resource of mouse lines with striking patterns of axonal labelling, which facilitates analysis of the normal wiring diagram of the brain. Studies of two of these mouse lines have identified an in vivo guidance function for a vertebrate transmembrane semaphorin, Sema6A, and have helped re-evaluate that of the Eph receptor EphA4.
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Acknowledgements
We thank R. Klein and colleagues for helpful discussions and sharing their results on EphA4 mutants; S. McConnell, A. Chédotal, J. Rubenstein and members of the Rubenstein laboratory for helpful discussions on mouse neuroanatomy; A. Smith, P. Mombaerts and T. Vogt for reagents; and P. Tate, P. Wakenight and J. Mak for technical support. Funding for this project was provided by grants to M.T.L. and W.C.S. from the NIMH, and to W.C.S. from the NICHD. M.T.L. was also supported by a 1999 Sandler Award in Basic Sciences, the Howard Hughes Medical Institute, and the HHMI Research Resources Program grant to the UCSF School of Medicine. W.C.S. was a 1998 Searle Scholar. P.A.L. is a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation, K.J.M. was supported by a fellowship from the Jane Coffin Childs Memorial Fund, and L.V.G. by a fellowship from the Helen Hay Whitney Foundation. X.L is a postdoctoral associate and M.T.L. an Investigator of the Howard Hughes Medical Institute.
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Leighton, P., Mitchell, K., Goodrich, L. et al. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410, 174–179 (2001). https://doi.org/10.1038/35065539
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DOI: https://doi.org/10.1038/35065539
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