This research unit's work focuses on neural circuit assembly. To circumvent the complexity evident in most nervous systems, together with the members of my laboratory, we are studying the development of a simple circuit formed, in part, by the connections between spinal motor neurons and limb muscles. In this context, we are studying the molecular processes underlying spinal motor axon guidance, motor neuron cell body migration within the ventral spinal cord and developmentally programmed motor neuron apoptosis. We are using genetic and cellular manipulations in mouse and chick to address the following specific questions:

Spinal motor neuron axon guidance:
We have identified ephrin:Eph tyrosine kinase receptor signalling as a major effector of motor axon guidance and our most recent experiments provide genetic evidence that Src-family kinases are important in relaying Eph signals in motor axon growth cones. Our observations also demonstrate that Netrin, a diffusible guidance cue, and its receptors Dcc, Neogenin and Unc5 are essential for motor axon guidance prompting us to address the question of how ephrin and Netrin signals are integrated in motor axon growth cones.

Neuronal migration:
We have recently shown that the Reelin signalling pathway is specifying the soma position of limb-innervating motor neurons within the ventral spinal cord. Our loss and gain of function studies provide intriguing evidence that Reelin is a competence factor enabling spinal motor neurons to migrate to their appropriate mediolateral position. In the long term, we will address the question of whether aberrant motor neuron soma location affects motor circuit function.

Motor neuron survival:
Motor neurons that innervate distinct muscles express specific combinations of neurotrophin receptors implying that motor neuron survival is controlled by combinatorial activity of neurotrophic survival factors. We are exploring this possibility by studying the expression of motor neuron survival factors in limb muscles and profiling motor neuron apoptosis in mouse mutants with altered limb patterning.