The human brain is highly organized and contains a myriad of 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 axon growth and guidance. Remarkably, however, few human disorders resulting from primary errors in these processes have been identified.
Using clinical data and genetic approaches in humans, our lab has identified the genetic basis of a series of congenital eye and facial movement disorders, and found that these genetic mutations disrupt specific steps in the development of ocular cranial motor neurons, extraocular muscle innervation, and connectivity. Thus, these disorders, referred to as the congenital cranial dysinnervation disorders (CCDDs), now provide a paradigm for us to study cranial motor neuron development and axon growth and guidance.
We have found that many CCDD genes are widely expressed yet confer a selective vulnerability to subsets of cranial motor neurons, particularly those that control eye movements. This is in contrast to many other motor neuron diseases, in which ocular motor neurons are selectively spared. We now want to understand—on a molecular level—how these motor neurons acquire distinct identities from other motor neuron populations and how their development is selectively disrupted in these disorders. We are addressing these questions through animal models, tractography, cellular and biochemical approaches, transcriptomics, and live cell and single-molecule imaging. We also continue to expand our research interests through the identification of new human syndromes and new disease genes.
Intriguingly, through what amounts to a human mutagenesis screen, we have uncovered several dominant disorders that result from recurrent missense mutations altering specific amino acid residues in cell signaling and cytoskeletal proteins. In some instances, different mutations within the same gene result in phenotypically distinct human syndromes. Therefore, we predict that these mutations affect sub-functions of the cytoskeleton and its associated proteins. By understanding how each of these sub-functions contributes to fundamental biology of the neuron, we can understand how the combination of these molecular pathways cooperates to specify proper connectivity.
As of March 23, 2016