Transcriptional regulation of neuronal morphogenesis

The polarized morphology of neurons is fundamental for the functioning of the nervous system. While the axon generally propagates action potentials toward the efferent neuron, dendrites receive and integrate information from afferent synaptic inputs. Morphology is therefore an essential determinant of the function of a neuron within the neuronal circuit. Of all cell types neurons display perhaps the most varied morphologies, with countless patterns of axonal projections and dendritic arborizations. How neurons adopt their type-specific morphologies in order to generate and maintain functional connections is a fundamental question in the field of neurobiology. Studies of neuronal morphogenesis have commonly distinguished between cell-extrinsic and cell-intrinsic mechanisms that regulate the growth of axons and dendrites. Although the extracellular signals that control the growth and patterning of dendrites are beginning to be characterized, the cell-intrinsic mechanisms that specify dendritic morphogenesis remain largely to be elucidated.; I have found that the genetic knockdown of the transcription factor NeuroD in granule neurons of the cerebellar cortex profoundly impaired the growth and maintenance of dendrites. Surprisingly, NeuroD knockdown simultaneously enhanced the growth of axons in primary cerebellar granule neurons. Although DNA binding was required for NeuroD's function in dendritogenesis, NeuroD inhibited axonal growth independent of its binding to DNA. In another line of experiments I found that NeuroD mediated neuronal activity-dependent dendritic morphogenesis. Downstream of neuronal activity CaMKII phosphorylated endogenous NeuroD at distinct sites, including Ser336 in primary neurons, thereby stimulating NeuroD-dependent dendritic morphogenesis. Together my results suggest that NeuroD orchestrates a cell-intrinsic transition from axonal growth to dendritic morphogenesis. My findings also define a novel CaMKII to NeuroD signaling pathway underlying activity-dependent dendritic growth of developing neurons that may play important roles in the plasticity of the adult brain.