Education
B.S. 1974, Massachusetts Institute of Technology
Ph.D.1979, Massachusetts Institute of Technology
Research Interest
FGF Homologous Factors: Regulators of Neuronal Function
We have discovered and are studying proteins called fibroblast growth factor homologous factors (FHFs). FHF gene mutations engineered in mice or occurring naturally in humans are associated with a range of neurological disorders. FHFs were discovered by virtue of their sequence homology to fibroblast growth factors (FGFs). While FGFs exert pleiotropic biological effects through interactions with their cell surface FGF receptors, we have demonstrated that FHFs are intracellular and bind to specific neuronal protein targets (click Figure 1 link below). Among these targets are a neuronal protein kinase scaffolding protein termed IB2 and the large family of alpha subunits for voltage-gated sodium channels.
FHFs and Sodium Channels
Our most comprehensive understanding of FHF function comes from studies on cerebellum. FHFs complex with voltage-gated sodium channels clustered at the axon initial segments of cerebellar granule cells (click Figure 2 link below). In granule neurons of mice lacking FHF1 and FHF4 proteins, sodium channels inactivate more readily, resulting in impaired neural firing and cerebellar function (ataxia) (click Figure 3 link below). These findings provide a physiological understanding for spinocerebellar ataxia syndrome associated with human Fhf4 mutation and suggest a broad role for FHFs in the control of excitability throughout the central nervous system. Ongoing research is exploring the mechanism by which FHFs control sodium channels and assessing the role of FHFs in sodium channel-dependent dendritic and axonal propagation of action potentials.
FHFs and IB2
IB2, another binding partner for FHFs, is a putative protein kinase scaffold protein expressed specifically in neurons. From studies in our lab and others, IB2 binds a group of proteins that appear to define a signal transduction pathway (click Figure 4 link below). However, activators and effectors of an IB2-scaffolded pathway are still unreported. We are investigating the biochemical and biological significance of IB2-scaffolded signaling by making use of IB2-/- mutant mice.
Selected Publications
Goldfarb, M., Schoorlemmer, J., Williams, A., Diwakar, S., Wang, Q., Huang, X., Giza, J., Tchetchik, D., Kelley, K., Vega, A., Matthews, G., Rossi, P., Ornitz, D.M., and D’Angelo, E. (2007). Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels. Neuron 55, 449-463.
Goldfarb, M. (2005) Fibroblast growth factor homologous factors: evolution, structure, and function. Cytokine Growth Factor Rev. 16, 215-220.
Olsen, S., Garbi, M., Zampieri, N., Eliseenkova, A.N., Ornitz, D.M., Goldfarb, M. and Mohammadi, M. (2003) FHFs share structural but not functional homology to FGFs. J. Biol. Chem. 278, 34226-34236.
Schoorlemmer, J. and Goldfarb, M. (2002) Fibroblast growth factor homologous factors and the islet brain-2 scaffold protein regulate activation of a stress-activated protein kinase. J. Biol. Chem. 277:29111-49119
Schoorlemmer, J. and Goldfarb, M. (2001). Fibroblast growth factor homologous factors are intracellular signaling proteins. Curr. Biol. 11, 793-797.
more publications in Biosketch link below
Links
BIOL370: Physiology of Nervous System
BIOL470.58/BIOL790.61: Cell Biology of the Nervous System,
INFORMATION for BIOL710: Molecular Biology
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GOLDFARB BIOSKETCH
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