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The human brain is a highly organized structure containing myriad axon tracts that follow precise pathways and make predictable connections. Model organism research has provided tremendous advances in our understanding of the principles and molecules governing the growth and guidance of these axons. Despite these advances, only a handful of human disorders clearly resulting from errors in these processes have been identified. Our lab has defined a series of such disorders through our studies of inherited congenital eye movement disorders now referred to as the congenital cranial dysinnervation disorders (CCDDs). Beginning with patients ascertained from around the world, we use clinical and neuroimaging approaches to define inherited human syndromes, genetic approaches to identify the underlying disease genes, and molecular approaches to study the role of these genes in normal and abnormal neurodevelopment. The disease genes we have identified to date highlight various steps essential to cranial motor neuron development and to axon growth and guidance, including mutations that result in loss of the axon guidance receptor ROBO3, gain-of-function of the RacGAP alpha2-chimaerin, and altered function of the anterograde kinesin KIF21A and the neuronal specific beta-tubulin isotype TUBB3. Thus, by identifying the genetic defects in these complex eye movement disorders, we are defining a series of genes essential to normal axon guidance in humans.

Current projects in the lab include (1) the use of mapping and next generation sequencing technologies to identify genes mutated in various central and peripheral nervous system developmental disorders, and (2) functional studies of these mutated genes and the roles of the normal and abnormal proteins in development, using mouse modeling and various in vitro approaches. We are particularly interested in the role of the cytoskeleton and the interplay between microtubules and their associated proteins in axon growth and guidance.

Last Update: 8/22/2013

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© 2013 by the President and Fellows of Harvard College