The search to understand the mechanisms regulating brain wiring has relied
on biochemical purification approaches in vertebrates and genetic approache
s in invertebrates to identify molecular cues and receptors for axon guidan
ce. Here we describe a phenotype-based gene-trap screen in mice designed fo
r 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 pattern
s of axonal labelling, which facilitates analysis of the normal wiring diag
ram 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.