Elizabeth C. Engle

Department of Neurology

Investigator, Howard Hughes Medical Institute
Children's Hospital Boston
Center for Life Science Building, 14th Floor
300 Longwood Avenue
Boston MA 02115
Tel: (617) 919-4030
Fax: (617) 730-0253
Email: elizabeth.engle@childrens.harvard.edu
Web Page: The Engle Lab Page

Web Page: The Engle HHMI Web Page

4 postdoctoral fellows, 1 graduate student

Our lab has two major areas of interests: (1) the development of cranial motor neurons and nerves and genetic disorders that perturb their normal development – the congenital cranial dysinnervation disorders (CCDDs); (2) the genetic basis of common forms of strabismus (‘squint’).  Cranial nerve disorders tend to be inherited as single gene disorders, while common strabismus is a complex genetic trait. 

We ascertain patients with these disorders both locally and world-wide. Study participants are carefully phenotyped, including ascertainment of medical and family history, exam details, magnetic resonance imaging, and neuropathological studies.  This approach has led to our definition of multiple new human malformation syndromes, including those with co-inheritance of additional developmental defects that have provided insight into the etiologies of more prevalent pediatric disorders such as mental retardation, autism, deafness, vascular defects, limb anomalies, and scoliosis.

We use linkage analysis and positional cloning techniques to identify genes mutated in the CCDDs. Consistent with our hypothesis, each of the disease genes we have identified appear to be essential to a specific step in the development of cranial motoneuron development, thus providing a paradigm for studying brainstem motoneurons, and motoneuron development in general. 

We explore the pathogenesis of selected CCDDs through in vitro and in vivo studies. Using genetic engineering technologies, we have made mice that carry specific CCDD mutations and recapitulate the human phenotypes, thus providing animal models for detailed analysis. We are focusing, in particular, on several CCDDs that appear to interfere with normal axon development by altering kinesin transport and microtubule and growth cone dynamics.

References:

• Tischfield MA, Bosley TM, Salih MAM, Alorainy IA, Sener EC, Nester MJ, Oystreck DT, Chan W-M, Andrews C, Erickson RP, Engle EC Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nature Genetics 2005;Oct;37(10):1035-7.
• Jen JC, Chan W-M, Bosley TM, Wan J, Carr JR, Rüb U, Shattuck D, Salamon G, Kudo L, Ou J, Lin DDM, Salih MAM, Kansu T, Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger J, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC. Mutations in a human robo gene disrupt hindbrain axon pathway crossing and morphogenesis. Science, 2004;304:1509-1513
• Yamada K, Andrews C, Chan W-M, McKeown CA, Magli A, de Berardinis T, Loewenstein A, Lazar M, O'Keefe M, Letson R, London A, Ruttum M, Matsumoto N, Saito N, Morris L, Del Monte M, Johnson RH, Uyama E, Houtman WA, de Vries B, Carlow TJ, Hart BL, Krawiecki N, Shoffner J, Vogel MC, Katowitz J, Goldstein SM, Levin AV, Sener EC,  Ozturk BT, Akarsu AN, Brodsky MC, Hanisch F, Cruse RP, Zubcov AA, Robb RM, Roggenkäemper P, Gottlob I, Kowal L, Ravi Battu R, Traboulsi EI, Franceschini P, Newlin A, Demer JL, Engle EC. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nature Genetics, 2003;35:318-321.