The vertebrate brain is made up of billions of nerve cells, called neurons, which relay and store information about their surroundings and experiences. This vast population of neurons is interconnected to build a multitude of circuitries that transmit information. Modulation of this complex neuronal network allows processing of information and invoke appropriate response . During the genesis of these circuitries, each neuron generally polarizes to form morphologically well-defined structures, namely an axon and multiple dendrites. The axon transmits messages to other neurons, sometimes over very long distances, whereas the dendrites receive messages from axons of other nerve cells. Proper formation of axons and dendrites is therefore important for information processing, and is crucial for nearly every aspect of neuronal function. The development of neuronal polarity (one axon and multiple dendrites) has been most extensively studied using cultured primary rat hippocampal neurons as a model system. Identifying the determinants that underlie axon formation and the development of polarity has been a major challenge. Recently, members of the Rho family of GTPases have emerged as key players in the establishment of neuronal polarity. These proteins function as 'switches', existing in both an active 'on' state and also an inactive 'off' state. This switch mechanism enables them to control many signaling pathways inside cells that in turn control the cell's activity, growth and cell shape. However, the underlying mechanisms by which Rho GTPases integrate signals and mediate their effects on neuronal polarity are still poorly understood. The group of Dr. Van Aelst has recently identified DOCK7 as a novel regulator of the Rho GTPases and has demonstrated a role for DOCK7 in axon formation and neuronal polarization using cultured hippocampal neurons. This project will define the cellular mechanisms by which DOCK7 contributes to the formation of an axon and neuronal polarity. In particular, the relationship between DOCK7 and the Rho GTPases and how their activities evoke the rapid elongation of the axon will be examined. Broader Impacts: This project will broaden the general understanding of the mechanisms underlying axon formation, which is fundamental to establishing how a neuron acquires its polarity and get integrated into a circuitry. Information gained from these studies will also provide further insights into how neurons communicate with each other. Finally, this work will help define the upstream signaling molecules triggering local Rho activation that in turn alter the cytoskeletal dynamics important for axon formation and neuronal polarization. Thus, this project will improve our understanding of fundamental cellular processes important for the establishment of neuronal polarity and cell polarity in general. This study will also make important educational contributions since graduate students will be involved in performing the research and high school students will be given the opportunity to learn how to carry out scientific research.
