Elizabeth Engle, M.D.
Professor of Neurology and Ophthalmology
F.M.Kirby Neurobiology Center
Center for Life Science, Room 14-075
3 Blackfan Circle
Boston, MA 02115
Visit my lab page here.
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 axon growth and guidance, including mutations in ROBO3, CHN1, and KIF21A. Individuals with the autosomal recessive disorder ‘horizontal gaze palsy with progressive scoliosis’ have uncrossed corticospinal and sensory tracts and pontine axons and harbor homozygous mutations in the axon guidance gene ROBO3 (Rig1). Mouse Robo3/Rig1 is required for midline crossing of axons in the hindbrain. Individuals with a complex strabismus disorder called Duane syndrome can harbor dominant gain-of-function mutations in CHN1 that hyperactive alpha2-chimaerin, a RacGAP signaling molecule downstream of axon guidance receptors. These mutations result in stalling of axons of the oculomotor and abducens cranial nerves. Individuals with another complex strabismus disorder called CFEOM1 harbor mutations in a very specific region of the stalk of the developmental kinesin, KIF21A. Kinesins are molecular motors that carry cargo along the microtubule cytoskeleton to the growth cone of a developing axon, and these dominant mutations in KIF21A appear to alter the delivery of KIF21A cargo to the developing extraocular muscles. 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. We have generated mouse loss- and gain-of-function models for several of these human disorders, and are using in vitro and in vivo approaches to investigate the function of the encoded proteins in normal and aberrant axon guidance.
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 embarking on both linkage analysis and association studies to identify genetic variants that put one at higher risk for common strabismus as well.
For a complete listing of publications click here.
Last Update: 11/7/2013