| During development of the nervous system, both activity-dependent and genetically determined mechanisms are required to establish proper neuronal connectivity. Initially connections are coarsely established, mostly by the actions of intrinsic factors, however activity is necessary for refining these connections and forming proper cortical maps. Although, immediate cellular effects of synaptic activity are mediated through the modification of pre-existing machinery in the cell, long-term changes in synaptic organization require activity-dependent transcription and synthesis of new proteins. Several transcription factors, CREB being the most notable, are required for experience dependent plasticity during development. However, a thorough screen to identify other factors has not been conducted previously. To identify such factors we took advantage of a novel expression cloning strategy designed to identify Ca 2+-inducible transcription activators. Among others, we cloned a previously known basic helix loop helix transcription factor named Neurogenic differentiation factor 2 (NeuroD2). We demonstrated that NeuroD2-mediated transcription could be activated by Ca2+ influx and by calcium/calmodulin-dependent kinase IV in cortical neurons. Furthermore, a mouse line with a targeted deletion of the NeuroD2 coding sequence displayed defects in developing somatosensory cortical maps. In these mice a failure to refine the organization of thalamocortical axon terminals resulted in lack of periphery-related maps in the somatosensory "barrel" cortex. Concomitant with defects in thalamocortical axon refinement, development of dendritic arbors in cortical neurons was also compromised in neuroD2 knockout cortical neurons. Taken together, our findings indicate that NeuroD2 is an activity-dependent transcription factor that is required for the normal development of the neocortex. |
