Cytoplasmic transport of organelles and macromolecules by molecular motors is of fundamental importance for the establishment and maintenance of cell polarity. In addition, defective motor transport is implicated in neurological diseases and pathogenic viruses and bacteria frequently exploit cellular transport routes. The challenge of studying microtubule-based transport is that movements are driven by large and complex macromolecular assemblies, with a single cargo often bound simultaneously by multiple opposite polarity dynein and kinesin motors.
Using a tractable model system in Drosophila embryos we have shed light on mechanisms responsible for polarised sorting of specific mRNA molecules by microtubule motors. We have revealed molecular links between localising mRNAs and dynein and used novel in vitro motility assays to show that long distance movement of the motor is activated by mRNA localisation signals. Together with Andrew Carter’s lab at the LMB, we have used purified mammalian proteins to show that the adaptor protein BicD is a key factor in switching on dynein processivity. We have also used in vitro approaches to investigate the molecular basis of mutations in Dynein heavy chain that cause neurological diseases in humans.
We have also been studying how cargo transport is orchestrated in neurons using the intact Drosophila nervous system as a model. We recently established a novel imaging assay in the adult wing and are using it to study the relationship between axonal transport and the healthy lifespan of neurons. We are also investigating how specific mRNAs are sorted into axons and dendrites in neurons, and how these processes contribute to neuronal development and function. We have developed optimised tools for CRISPR genome engineering in Drosophila, and are using these in several projects. You can read more about our CRISPR tools, and how to obtain them, here.
Future goals include:
To isolate novel components of cargo transport complexes and characterise their functions in microtubule-based transport processes.
To understand how opposite polarity motors operate on a single cargo during polarised sorting and why this seemingly inefficient mechanism of transport has been selected for.
To elucidate the structural basis of cargo recognition and how a model motor:cargo complex is assembled.
To understand how the assembly and disassembly of cargo-transport complexes is regulated in time and space within cells.
To gain insights into how transport processes contribute to neuronal function and dysfunction.