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Researcher | Research Overview

My lab investigates aberrant cranial motor neuron development by identifying human congenital disorders of eye and face movement, defining their genetic etiologies, and uncovering their molecular pathways and disease mechanisms. Cranial motor neurons provide a unique and powerful system to study neuronal connectivity because of the small number of motor neurons within distinct nuclei and the straightforward tractable trajectories of their axons that can be visualized in three dimensions. Moreover, errors in their development result in visible, reproducible human phenotypes that consistently translate to mouse and zebrafish models.

Our research focuses on genes essential to the development of the cranial nerves, a diverse group of sensory and motor nerves originating in the brain that control our ability to see, hear, taste, smell and carry out a number of other essential functions. Mutations in these genes can cause complex eye-movement disorders, facial weakness, deafness, loss of smell (anosmia), and difficulties with swallowing and respiration. Some individuals with these symptoms may also have other motor, sensory, intellectual, behavioral and social disabilities. My lab has defined the clinical manifestations and identified the genetic causes of a series of such disorders, now referred to as the congenital cranial dysinnervation disorders (CCDDs), including: congenital fibrosis of the extraocular muscles (CFEOM) types 1-3, Duane syndrome, Duane radial ray syndrome, horizontal gaze palsy, and atypical forms of Moebius syndrome. These disorders can result from mutations in genes critical to motor neuron development or that alter the ability of the axon to grow normally, resulting in stalled growth or inappropriate guidance. We have also identified several disorders that selectively impair the development of extraocular or facial muscle.

Major projects in the lab include (1) interpretation of >900 whole genome sequences from families with congenital disorders of eye and face movement, focusing on noncoding and structural variation as well as coding variants; (2) functional and mechanistic studies of genetic variants and their normal and abnormal proteins using mouse and zebrafish modeling, stem cell differentiation to the cell types of interest, and in vitro approaches, (3) studies of embryonic wildtype and mutant cranial motor neurons through single cell RNA sequencing, in situ studies, and mouse and zebrafish gene manipulations. These studies are defining: how these motor neurons acquire distinct identities, form cranial nuclei and subnuclei, and target specific cranial musculature; how these processes are disrupted in human development resulting in birth defects; and why these motor neurons are selectively vulnerable to or spared in specific neurodevelopmental and neurodegenerative disorders.

Researcher | Research Background

Elizabeth Engle is a Professor of Neurology and Ophthalmology at Harvard Medical School, an Investigator of the Howard Hughes Medical Institute, and an Associate Member of the Broad Institute of MIT and Harvard. At Boston Children's Hospital, she is a member of the Departments of Neurology, Ophthalmology and Medicine (Genetics), a member of the F.M. Kirby Neurobiology Center and the Program in Genomics, and a senior investigator for The Manton Center for Orphan Disease Research. Dr. Engle received her B.A from Middlebury College and her M.D. from Johns Hopkins University School of Medicine. She trained in pediatrics at Johns Hopkins, in neuropathology at Massachusetts General Hospital, and in adult and child neurology in the Longwood Neurology Training Program and at Boston Children's Hospital. Following her residencies, she was a research fellow with Louis Kunkel, Ph.D., and later Alan Beggs, Ph.D., in the Division of Genetics at Children's prior to establishing her own research lab in 1997. Her work has defined the human congenital cranial dysinnervation disorders and has been recognized by high-profile publications and by receipt of multiple honors, including the E. Mead Johnson Award for Research in Pediatrics from the Society for Pediatric Research, the Sidney Carter Award in Child Neurology from the American Academy of Neurology, and a Research Award for Vision from the Alcon Institute. In addition to her research, Dr. Engle continues to care for patients, primarily consulting for children and adults with rare eye and facial movement disorders and other cranial nerve disorders. She teaches in both the clinical and laboratory settings, and has served on multiple committees that set the direction for neuroscience and ophthalmology research locally and nationally.


Researcher | Publications