The basic architecture of the cerebral cortex consists of neurons arranged in six layers. This architecture reflects the organisation of projections where pyramidal projection neurons sent efferent axons to distant subcortical targets or to other cortical regions. Collaterals of pyramidal cell axons, form stereotyped connections within and between laminae. For instance pyramidal cells in layers 2/3 elaborate axon collaterals in layers 2/3 and 5 but not layers 4 and 6. Similarly, layer 6 cells extend axon collaterals within their layer that ascend and branch in layer 4 but not in layer 5. In addition deep layer neurons of each area send their axons over long distances towards a specific thalamic nucleus. Although it is generally believed that extracellular signals, (attractants or repellents) that act either at a short range or at a long range are detected by the growth cones and are used as guidance cues, little is known about the cellular and molecular mechanisms that lead to the formation of such highly specific connections. Some ideas about the overall nature of those mechanisms can be found in studies of other systems such as the regulation of the pattern of synaptic connections in Drosophila. For instance, Dr. L. Zipurski and his colleagues have demonstrated in a series of publications that the axons of the photoreceptors R1-R6 do not select their targets in the optic lobe by recognising a simple “stop” signal that is presented to them. It appears that cross communication between them is also necessary. Screening for genes that might be part of this mechanism they found that a gene called flamingo is crucial in regulating target selection of distinct classes of photoreceptors in the developing ommmatidia. Flamingo encodes for a seven-pass transmembrane cadherin and is part of a signalling pathway that interprets a polarity cue and polarises cells along their planar axis. The acquisition of this lateral polarity is known as Planar Cell Polarity (PCP) or tissue polarity. In vertebrates, the PCP pathway has been shown so far to regulate convergent extension movements (early in embryogenesis) and neural tube closure, as well as the orientation of stereociliary bundles of sensory hair cells in the inner ear. We are currently investigating if the PCP pathway is similarly involved in the development of cortical axons and their target selection. To do so, we analyze the phenotype of the corticothalamic connections in animals that carry a gene knock out, or in transgenic animals in which specific genes are silenced by a Cre inducible RNAi approach.