Return to list Elizabeth Engle, MD
Elizabeth Engle, MD
Professor of Neurology and Ophthalmology, Harvard Medical School
Senior Associate in Neurology, Boston Children’s Hospital
Boston Children's Hospital
300 Longwood Avenue
Boston, MA 02115
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 encode proteins that, when mutant, alter various steps in growth cone signaling and cytoskeletal function essential to axon growth and guidance. These include loss of the transmembrane guidance receptor ROBO3, and perturbations to the Rac-GAP alpha2-chimaerin, the anterograde kinesin KIF21A, and the TUBB3 and TUBB2B beta-tubulin components of the microtubule itself.
Genetic projects in the lab include the use of exome and genome sequencing to identify human CCDD genes, as well as genotype-phenotype studies of disorders we have defined. The lab is also studying the genetic contributions to more common forms of strabismus such as esotropia and exotropia (lazy eye). These forms of strabismus are not typically inherited in a Mendelian fashion, but do run in families and appear to be inherited as complex genetic traits. Thus, we are conducting genetic studies to identify variants that put one at higher risk for common strabismus as well. Neurodevelopmental and cell biological projects in the lab focus on the molecular mechanisms underlying the CCDDs. We have generated loss- and gain-of-function mouse models for multiple CCDDs, and are using in vitro and in vivo approaches to investigate the function of the encoded proteins in normal and aberrant axon guidance. We have developed techniques to visualize developing nerves in order to define their fine-tuned targeting decisions and determine how they are perturbed by human mutations. We are also exploring the basis for selective vulnerability of specific motor neuron populations to mutations that alter widely expressed genes.
- R01 EY15298
Howard Hughes Medical Institute