Genetic Specification Of Thalamocortical Projections

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DESCRIPTION (provided by applicant): The topographic projection of each thalamic nucleus to a unique set of cortical areas underlies the input specificity characterizing each sensory modality. Although the importance of the patterning of thalamocortical projections for normal brain function has long been appreciated, the underlying developmental mechanisms remain largely unknown. The aim of this project is to identify the key molecular cues patterning thalamocortical projections in mammals. We recently obtained evidence demonstrating that (i) topographic cues present in an intermediate target, the ventral telencephalon, play a critical role in the sorting of thalamocortical projections to distinct cortical domains and (ii) that the bHLH transcription factor Neurogenin2 specifies cell-autonomously the topography of thalamic projections by controlling axon responsiveness to the intermediate cues present in the ventral telencephalon. Based on these preliminary results, the following Specific Aims will be carried out: 1. Determine the role of the ventral telencephalon in the patterning of thalamic axons projections to distinct cortical domains using a new 'whole-mount' in vitro assay recapitulating some of the key aspects of the topography of thalamic axon projections observed in vivo. 2. Determine the role of Neurogenin2 in the specification of the topography of thalamocortical projection. We will test the spatial and temporal requirement of Ngn2 expression in the specification of thalamic neurons connectivity using a gain-of-function approach where full-length Ngn2 or interfering constructs will be ectopically or heterochronically expressed in the dorsal thalamus using an electroporation-mediated gene transfer. 3. Isolate and characterize the transcriptional targets of Neurogenin2 in the developing thalamus. We will identify the set of genes controlled transcriptionally by Ngn2 and involved in the patterning of thalamic axon projections using both a candidate approach and an unbiased genome-wide approach.