501D Life Sciences Building
Neurotrophic factors are proteins that are traditionally known to influence survival and function of neurons in the central and peripheral nervous systems. Recent studies, however, have shown that specific neurotrophic factors may cause neuronal death instead of survival, depending upon which receptors and signaling pathways are activated. When these factors activate their receptor tyrosine kinase, the Trk receptors, they promote neuronal survival, axonal growth, and support many aspects of neuronal function. However, when these factors activate the p75 neurotrophin receptor, they can elicit neuronal death, axonal retraction and degeneration. We are examining mechanisms governing death- vs. survival-promoting actions of nerve growth factor and related neurotrophins during development and under conditions of brain injury. Although the p75 neurotrophin receptor can evoke neuronal death in the context of brain injury, we find that in the developing brain, this receptor can regulate proliferation of neuronal progenitor cells. Thus, we find that these factors have different functions depending on the cellular context.
Work in my lab investigates specific cellular mechanisms of neurotrophin actions on CNS neurons and glia during development and after brain injury. We use primary cultures of embryonic neurons to investigate mechanisms by which specific trophic factors influence neuronal survival, differentiation or degeneration. We also use in vivo models of brain injjury to determine how these factors regulate survival or degeneration under these conditions. Our work is geared to understanding how these factors affect neuronal survival and function, development and degeneration, and how they may ultimately influence neuronal survival under inflammatory conditions associated with disease and injury in the brain.
B.A., Oberlin College, 1979.
Ph.D., The Rockefeller University, 1986.
Montroull, L.E., D. Rothbard, H.D. Kanal, V. D'Mello, V. Dodson, C.M. Troy, J.P. Zanin, S.W. Levison, and W.J. Friedman, Proneurotrophins induce apoptotic neuronal death after controlled cortical impact injury in adult mice, ASN Neuro, 12: 1-13, https://doi.org/10.1177/1759091420930865, 2020
Zanin, J.P., L.E. Montroull, M. Volosin, and W.J. Friedman, p75NTR modulated TrkB trafficking and signalling in response to BDNF treatment in hippocampal neurons, Frontiers in Cellular Neuroscience, https://doi.org/10.3389/fncel.2019.00485, 2019
Zanin, J.P., J. Verpeut, Y. Li, M.W. Shiflett, S.-S. Wang, V. Santhakumar, and W.J. Friedman, The p75NTRinfluences cefebellar circuit development and adult behavio via regulation of cell cycle duration of granule cell progenitors, J. Neurosci. 39 (46): 9119-9129, https://doi.org/10.1523/JNEUROSCI.0990-19.2019, 2019
Saadipour, K., A. Tiberi, S. Lomardo, L. Montroull, N. Manucat, J. LaFancois, M. Cammer, P. Mathews, H. Scharfman, F.-F. Liao, W. Friedman, X.-F. Zhou, G. Tesco, and M. Chao, REgulation of BACE1 expression after injury is linked to the p75 neurotrophin receptor, Mol. Cell Neurosci., 99, https://doi.org/10.1016/j.mcn.2019.103395, 2019
Cragnolini, A.B. G. Montenegro, W.J. Friedman, and D.H. Masco, Brain-region specific responses of astrocytes to an in vitro injury and neurotrophins, Mol. Cell. Neurosci, 88: 250-248, https://doi.org/10.1016/j.mcn.2018.02.007, 2018
Greenwood, S.G., L. Montroull, M. Volosin, H.E. Scharfman, K.K. Teng, M. Light, R. Torkin, F. Maxfield, B.L. Hempstead, and W.J. Friedman, A novel neuroprotective mechanism for lithium that prevents association of the p75NTR-sortilin receptor complex and attenuates proNGF-induced neuronal death in vitro and in vivo, eNeuro 5 (1) : https://doi.org/10.1523/ENEURO.0257-17, 2017
Zanin, J.P., E. Abercrombie, and W.J. Friedman, Proneurotrophin-3 promotes cell cycle withdrawal of developing cerebellar granule cell progenitors via the p75 neurotrohin receptor, eLife, 10.7554/eLife.16654, 2016
VonDran, M.W., J. LaFrancois, V.A. Padow, W.J. Friedman, H.E. Scharfman, T.A. Milner, and B.L. Hempstead, ProBDNF, but not proNGF, is upregulated following seizures in mice, ASN Neuro, 10.1177/1759091414552185, 2014
Friedman, W.J. A.P. Le, S. Choi, and M. Volosin, Seizures tip the balance of neurotrophin signaling toward neuronal death, in Handbook of Neurotoxicology "Physiology and pathophysiology of neurotrophins" (R.M. Kostrzewa, ed) Springer, pp. 1945-1953, 2014
Choi, S. and W.J. Friedman, Interleukin-1ß enhances neuroal vulnerability to proNGF-mediated apoptosis by increasing surface expression of p75NTR and sortilin, Neuroscience, 257: 11-19, 2014
Cragnolini, A.B., Volosin, M., Huang, Y.Y., and W.J. Friedman WJ. Nerve growth factor induces cell cycle arrest of astrocytes. Dev Neurobiol. 72(6):766-776, 2012.
Pichardo-Casas, I., Goff, L.A., Swerdel, M.R., Athie, A., Davila, J., Ramos-Brossier, M., Lapid-Volosin, M., Friedman, W.J., Hart, R.P., and L. Vaca. Expression profiling of synaptic microRNAs from the adult rat brain identifies regional differences and seizure-induced dynamic modulation. Brain Res. 1436:20-33, 2012.
Le, A.P., and W.J. Friedman. Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures. J. Neurosci. 32(2):703-712, 2012.
Huang, Y.Y., Smith, D.E., Ibanez-Sandoval, O., Sims, J.E., and W.J. Friedman. Neuron-specific effects of Interleukin-1 beta are mediated by a novel isoform of the IL-1 receptor accessory protein. J. Neurosci. 31(49):18048-18059, 2011.
Song, W., Volosin, M., Cragnolini, A.B., Hempstead, B.L., and W.J. Friedman, ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons, J Neurosci. 30(46):15608-15615, 2010.
W.J. Friedman, Proneurotrophins, seizures, and neuronal apoptosis, Neuroscientist 16(3): 244-252, 2010.