Simon Halegoua was awarded a B.S. degree in Biochemistry at Stony Brook University in 1974 and continued on to receive a Ph.D. in Molecular Biology in 1978. He was a postdoctoral fellow in Molecular Neurobiology at the Salk Institute from 1978 to 1982. In 1982, he joined the faculty of the Department of Neurobiology & Behavior at Stony Brook University as Assistant Professor and was promoted to Associate Professor with tenure in 1988. In 1994 he was promoted to Full Professor. He served as Interim Chair of the Department from 2006-2008. Professor Halegoua has served as the Director of the Center for Nervous System Disorders since 2002. He served on the Editorial Boards of the Journal of Neuroscience and the Journal of Biological Chemistry.
The survival and function of all neurons are controlled by families of neuronal growth factors, which send retrograde signals across the synapse and up the axon, to reach the cell nucleus in the soma. The best-studied family of neuronal growth factors is the Neurotrophins (NTs), including the prototypic Nerve Growth Factor (NGF). The NTs control neuronal phenotype including axon growth, the cell cycle, neurotransmitter metabolism, electrophysiological characteristics and synaptic strength. Signaling from the NT receptor, Trk, involves the initiation of multiple signaling cascades that culminate in post-translational control of protein function, as well as translational and transcriptional controls of gene expression. Our lab has worked to dissect the signal transduction pathways for NT actions using a neuronal cell line, PC12, and in primary cultures of peripheral and central neurons from rat and mouse. We discovered the Ras proto-oncoprotein signaling pathway underlying NGF actions and continue to define this and the phospholipase C (PLC-gamma) pathways using biochemical and molecular approaches. These branched pathways independently mediate gene inductions leading to the differential establishment of neuronal phenotypic characteristics, such as the action potential, axon growth, or the expression of neuronal specific genes. One outcome of our studies was the discovery of the Na channel gene encoding PN1/NaV1.7/SCN9a, which carries the signal for pain in sensory axons of peripheral neurons, and is presently a major drug target for novel analgesics.
A central question for NT signaling lies in the differential signaling capability over time and space. Differential signaling is mediated by NT acting over seconds vs. minutes or hours. For example, we showed that pulsatile (60 sec) NT signaling selectively acts through PLC-gamma to increase expression of PN1/NaV1.7/SCN9a, to enhance neuronal excitability, while long-term (hours and days) signaling distinguishes NGF from mitogenic EGF signaling to control neuronal phenotype and survival. NTs must also signal biochemically from the nerve terminal over long axonal distances to the soma. We first proposed a now well-accepted model for this signaling via endosomal vesicles containing NT and Trk. We have identified the first molecular component, Pincher, for forming and trafficking these signaling endosomes. Using cell biological techniques including fluorescence confocal and immuno-electron microscopy along with Quantum Dot nano-crystals, we have been characterizing the mode by which Pincher mediates long-distance and long-term signaling and the biochemical nature of these signals generated in neurons.
- Thomas, S. M., DeMarco, M., D'Arcangelo, G., Halegoua, S., and Brugge, J.S. (1992) Ras Is Essential for Nerve Growth Factor- and Phorbol Ester-Induced Tyrosine Phosphorylation of MAP Kinases. Cell 68, 1031-1040.
- Wood, K. W., Qi, H., D'Arcangelo, G., Armstrong, R.C., Roberts, T.M. and Halegoua, S. (1993) The Cytoplasmic Raf-1 Oncogene Induces the Neuronal Differentiation of PC12 Cells: A Potential Role for Cellular Raf-1 in Neuronal Growth Factor Signal Transduction. Proc. Natl. Acad. Sci. USA 90, 5016-5020. [pdf]
- D'Arcangelo, G. and Halegoua, S. (1993) A Branched Signaling Pathway for Nerve Growth Factor Is Revealed By Src-, Ras-, and Raf-Mediated Gene Inductions. Mol. Cell Biol. 13, 3146-3155.
- Toledo-Aral, J.J., Brehm, P., Halegoua, S. and Mandel, G. (1995) A Single Pulse of Nerve Growth Factor Triggers Long Term Neuronal Excitability Through Sodium Channel Gene Induction. Neuron 14: 607-611.
- Rusanescu, G., Qi, H., Thomas, S.M., Brugge, J.S., and Halegoua, S. (1995) Calcium Influx Induces Neurite Growth Through a Src-Ras Signaling Cassette. Neuron 15: 1415-1425.
- Choi, DY, Toledo-Aral, JJ, Segal, R., and Halegoua, S. (2001). Sustained signaling by phospholipase C-gamma mediates nerve growth factor-triggered gene expression. Mol. Cell. Biol. 21: 2695 - 2705.
- Shao, Y., Akmentin, W., Toledo-Aral, J.J., Rosenbaum, J., Valdez, G., Cabot, J.B., Hilbush, B.S., and Halegoua, S. (2002) Pincher, a pinocytic chaperone for nerve growth factor/TrkA signaling endosomes. J. Cell Biol. 157: 679 – 691.
- Valdez, G., Akmentin, W., Philippidou, P., Kuruvilla, R., Ginty, D.D., and Halegoua, S. (2005) Pincher-mediated Macroendocytosis Underlies Retrograde Signaling By Neurotrophin Receptors. J. Neurosci. 25:5236 –5247. [pdf]
- Valdez, G., Philippidou, P., Rosenbaum, J., Akmentin, W., and Halegoua, S. (2007) Trk Signaling Endosomes Are Generated By Rac-dependent Macroendocytosis. Proc. Natl. Acad. Sci. USA, 104:12270-5. [pdf]
- Joset A, Dodd DA, Halegoua S, Schwab ME. (2010) Pincher-generated NogoA endosomes mediate growth cone collapse and retrograde signaling. J Cell Biol. 188:271-85.
- Philippidou P, Valdez G, Akmentin W, Bowers WJ, Federoff HJ, Halegoua S. (2011) Trk retrograde signaling requires persistent, Pincher-directed endosomes. Proc. Natl. Acad. Sci. USA 108:852-7.
- Harrington AW, St. Hillaire C, Zweifel LS, Glebova NO, Philippidou P, Halegoua S and Ginty DD. (2011) Recruitment of Actin Modifiers to TrkA Endosomes Governs Retrograde NGF Signaling and Survival. Cell 146:421-434.
Pubmed Linked Publications
- Tanvir Khan - Graduate Student
- Wendy Akmentin - Research Technician