Development and guidance of cranial motor neurons in health and disease

Dr. Engle's lab has defined a series of rare human syndromes we named the congenital cranial dysinnervation disorders in which mutations in genes critical to ocular motor neuron development lead to paralytic strabismus. We continue to identify sets of biologically informative point mutations underlying additional CCDDs, and have found that mutations in several CCDD genes alter the neuronal cytoskeleton directly (e.g., mutations in different tubulin isotypes) or indirectly (e.g., through cell signaling and motor transport), ultimately leading to errors in axon growth and guidance. Using HHMI finding, we are now connecting human neurological defects to molecular mechanisms of motor neuron and axon development. Our approach couples gene discovery with studies of key developmental processes in humans and model organisms. In addition, while we continue to study CCDDs and cranial axon growth and guidance, tools gained from developing this research program enable us to address additional clinically important topics in nervous system disease biology. First, we are elucidating complex genetic and neurodevelopmental basis of common forms of strabismus. Second, we aim to understand the molecular regulation of ocular motor neuron development, and how this differs from that of other motor neuron types. In doing so, we hope to learn why ocular motor neurons are selectively vulnerable in CCDDs, but spared in other disorders such as spinal motor atrophy (SMA) and amyotrophic lateral sclerosis (ALS), and thus gain insight into motor neuron subtype biology, disease mechanism, and potential therapies.