Tom Dockendorff, Ph.D.

 

Research Statement

Mental retardation (MR) is diagnosed in 1-3% of individuals from developed countries, a frequency that makes it one of the most common disorders of neural function.  The causes of MR are diverse, but a genetic etiology is suspected in a sizable fraction of cases.  MR patients can receive counseling to help support management of day-to-day living, but for the vast majority of MR cases, drug-based remedies that have restorative effects on cognition are non-existent.  

Understanding the misregulation of cellular physiology that elicits MR phenotypes is needed for rational development of therapeutic strategies, and the forms of MR that result from single gene mutations provide the best opportunities for success in this endeavor.  A model for this type of effort is the fragile X syndrome, a prominent form of heritable mental retardation that results from mutation of the FMR1 gene.  It is now recognized that the RNA-binding fragile X mental retardation protein (FMRP) facilitates trafficking of select mRNAs to post-synaptic compartments and regulates their translation in response to synaptic stimulation.  Indeed, the finding that FMRP activity is modulated by signaling through metabotropic glutamate receptors (mGluR) has enabled the use of mGluR antagonists as a therapy for fragile X syndrome.  Despite this advance, precise mechanisms of how FMRP contributes to post-synaptic protein synthesis remain unknown, and there is evidence that FMRP participates in gene regulation pathways that may not be linked to signaling through mGluRs.  The identification of these pathways may provide additional avenues for fragile X therapy.

The use of molecular genetics is a powerful means to discover pathways in which a gene of interest functions.  The genome of the fruit fly Drosophila melanogaster encodes an orthlogue of FMRP (dFMRP) that has considerable conservation in structure and function with its mammalian counterparts.  Over the last several years, my colleagues and I have used fly genetics to model fragile X syndrome.  Upon demonstrating that mutation of dfmr1 elicits phenotypes in the central nervous system with striking parallels to those observed in fragile X patients and mouse models, we have expanded our studies to uncover novel pathways that it modulates and insights into its function.  Among these efforts is one of the first demonstrations of the promise that mGluR antagonists have for fragile X therapy.  Our studies continue, with hopes of discovering other new functions by which FMRP modulates cognition.  

A significant majority of human genes that mutate to a MR phenotype have orthologues in the fly.  The success of the fly fragile X model suggests that similar studies with other candidate MR genes will be productive, and thus I plan to establish other fly models that may recapitulate other MR syndromes.  It is expected that the studies of such genes will provide both basic insights into neuronal function and help place these genes/proteins into biochemical pathways that may be targets for pharmacological therapy.

Related publications

Banerjee, P., Schoenfeld, B.P., Bell, A.J., Choi, C.H., Bradley, M.P., Hinchey P., Kollaros, M., Park J.H., McBride, S.M.J., and Dockendorff, T.C.
(2010) Short and long-term memory are modulated by multiple isoforms of the fragile X mental retardation protein. J. Neurosci. 30:6782-6792.

Banerjee, P., Nayar, S., Hebbar, S., Fox, C.F., Jacobs, M.C., Park, J.H., Fernandes, J.J., and Dockendorff, T.C. (2007) Substitution of critical isoleucines in the KH domains of Drosophila fragile X protein results in partial loss of function phenotypes.  Genetics 175:1241-1250.

Mc Bride, S.M.J.,  Choi, C.H., Wang, Y., Liebelt, D., Braunstein, E., Ferreiro, D., Sehgal, A., Siwicki, K.K., Dockendorff, T.C., Nguyen, H.T., McDonald, T.V., and Jongens, T.A. (2005) Pharmacological rescue of synaptic plasticity, courtship behavior and mushroom body defects in a Drosophila model of Fragile X Syndrome.  Neuron 45:753-764.

Costa, A., Wang, Y., Dockendorff, T.C., Erdjument-Bromage, H., Tempst, P., Schedl, P., and Jongens, T.A. (2005) The Drosophila Fragile-X protein functions as a negative regulator in the orb autoregulatory pathway.  Dev. Cell 8:331-342.

Zarnescu, D.C., Jin, P., Betschinger, J., Nakamoto, M., Wang, Y., Dockendorff, T.C., Feng, Y., Jongens, T.A., Sisson, J., Knoblich, J.A., Warren, S.T., and Moses, K. (2005) Fragile X protein functions with Lgl and the PAR complex in flies and mice.  Dev. Cell 8:43-52.

Dockendorff, T.C., Su, H.S., McBride, S.M.J., Yang, Z., Choi, C.H., Siwicki, K.K., Sehgal, A., and Jongens, T.A. (2002) Drosophila lacking dfmr1 activity show defects in circadian output and fail to maintain courtship interest.  Neuron 34:973-984.

Wan, L., Dockendorff, T.C., Jongens, T.A., and Dreyfuss, G. (2000) Characterization of dFMR1, a Drosophila melanogaster homolog of the fragile-X mental retardation protein.  Mol. Cell. Biol.  20:8536-8547.

 

Contact Information

Office:
M407 Walters Life Sciences
1414 West Cumberland Avenue
Knoxville, TN 37996-0840

Phone: (865) 974-5148
Email: tdockend@utk.edu