The development of functional neural circuits requires the formation and maintenance of long neuronal projections known as axons. These processes can extend long distances from the cell body. For instance, in humans the axons of the sciatic nerve extend over a meter on average, reaching from the caudal spinal cord to the toes. To form and support this large cell volume, proteins and organelles must be actively transport along the length of the axon. Consequently, defects in this ‘axonal transport’ are linked to many developmental and degenerative diseases of the nervous system. The primary goal of the Drerup lab is to understand how axonal transport of specific cargos is regulated and, in turn, how disruptions lead to axonal defects.
Of particular interest to us, is the unidirectional movement of various cargos by the cytoplasmic dynein motor. This single motor protein complex accomplishes the vast majority of cell body-directed transport: So how is specificity between motor and cargo is accomplished? Complimentarily, mutations in dynein and dynein-related proteins have been linked to diseases of the nervous system. Therefore, understanding how this motor moves an array of cargo in a regulated fashion will lend insight not only into the mechanistic regulation of intracellular transport but may also shed light on the pathology of diseases of the nervous system.
Due to their rapid development, translucent bodies, and amenity to genetic manipulations, zebrafish are an ideal system for this work. Forward and reverse genetics can be used to find novel genes important for intracellular transport and screen disease-related genes respectively. In addition, individual zebrafish embryos can be engineered to express fluorescently tagged cargos in neurons and their active transport can be imaged in real time in intact embryos or larvae. Together, these genetic manipulations allow us to dissect the mechanisms of intracellular transport in an intact, functioning neural circuit.