[ST6]: UNC‐129 acts in the UNC‐5/UNC‐6 pathway to regulate axon guidance

In the mammalian forebrain, the topographic projection of each thalamic nucleus to a unique set of cortical areas underlies the input specificity characterizing each sensory modality. Recent evidence has demonstrated that the inter-areal topography of thalamocortical (TC) axon projections is initiated before they reach the cortex, at the level of their main intermediate target, the ventral telencephalon. However, the molecular mechanisms leading to the topographic sorting of TC axons in the ventral telencephalon are poorly understood. Here, we demonstrate that Netrin1 is expressed in a high-rostral to low-caudal gradient in the mantle region of the ventral telencephalon and that it is both necessary and sufficient to control the topographic sorting of TC axons to distinct cortical territories. We found that Netrin1 knockout mice show a complete lack of topography of TC projections in the ventral telencephalon. Interestingly, we demonstrate that Netrin1 act as a chemoattractive cue for axons originating from the rostral thalamus and at the same time as a chemorepulsive cue for axons originating from the caudal thalamus. These results not only provide new insights into the molecular and cellular mechanisms specifying the topography of thalamocortical projections but they also provide the first in vivo demonstration that the secreted ligand Netrin1 can control the topography of projection of large ensembles of axons, a function so far almost exclusively attributed to the membrane-bound ephrin/Eph signaling system. We are currently exploring the receptors that could mediate the differential responsiveness of distinct thalamic axon subpopulations to Netrin1 in the ventral telencephalon. This work was supported by a grant from NIH/NINDS (NS047701-01) to FP as well as the March of Dimes Foundation for Borth Defects (FP).