• Researcher Profile

    Rosalind A. Segal, MD, PhD

     
    Rosalind A. Segal, MD, PhD
     
    Professor of Neurobiology, Harvard Medical School

    Office phone: 617-632-4737
    Fax: 617-394-2936
    Email: rosalind_segal@dfci.harvard.edu

    Preferred contact method: email
     
     

    Research Departments

    Cancer Biology

    Pediatric Oncology

    Area of Research

    Growth Factors in Central Nervous System Development and Oncogenesis


    Dana-Farber Cancer Institute
    450 Brookline Avenue
    Smith 1058A
    Boston, MA 02215

    Biography

    Dr. Segal received her PhD in 1985 from Rockefeller University and her MD in 1986 from Cornell University Medical College, followed by a residency in the Harvard Neurology Program. As a postdoctoral fellow at Massachusetts Institute of Technology, she investigated the role of nerve growth factors in regulating cerebellar development and tumor formation. She joined DFCI in 1998, where she is principally involved in laboratory research on nervous system development.

    Recent Awards

    • American Association of Physicians, 2011
    • Ted Williams Senior Investigator, Dana-Farber Cancer Institute, 2009
    • NIH Director's Pioneer Award, 2006
    • McDonnell Foundation Award, 2001
    • Pediatric Brain Tumor Foundation Award, 2001
    • Claudia Adams Barr Investigator, Barr Foundation, 1998
    • Robert Ebert Clinical Scholar Klingenstein Award, 1996
    • Dana Foundation Postdoctoral Fellowship, 1990
    • Medical Science Training Program Pre-doctoral Fellowship, 1980
    • National Science Foundation Pre-doctoral Fellowship, 1979
    • Phi Beta Kappa, Harvard College, 1979
    • Summa Cum Laude, Harvard University, 1979
    • National Merit Scholarship, 1975

    Research

    Growth Factors in Central Nervous System Development and Oncogenesis

    Our lab is interested in mechanisms whereby extracellular stimuli regulate proliferation and survival in the developing nervous system.

    Neurotrophin Signaling

    In order for target-derived neurotrophins to regulate the survival of a developing presynaptic cell, a signal must be propagated from the nerve terminal along the axon to the nucleus. We found that activated Trk receptors function as rapid retrograde signal carriers to elicit neuclear responses to target derived neurotrophins. Our data indicate that the mechanism of signal propagation is retrograde vesicular transport of activated Trk-ligand complexes. Once they reach the cell body, activated receptors elicit nuclear responses-including phosphorylation of the transcription factor CREB and subsequent induction of the immediate early gene c-fos.

    We are currently studying other intermediates required for retrograde signaling and the potential differences in the biological responses to retrograde or local stimulation with growth factors.

    Neurotrophins & Cancer

    While our studies have highlighted the role of BDNF in normal cerebellar development, we have also demonstrated that neurotrophins, in particular NT3, have a role in cerebellar diseases.

    Unregulated growth of cerebellar granule neuronal precursors results in formation of a tumor, known as medulloblastoma. We have found the NT3 receptor TrkC is expressed in these tumors, and that the level of expression is a prognostic indicator for clinical progression. Furthermore, our data show that NT3 induces an apoptotic response in meullobastoma tumor cells, indicating that neurotrophins have potential application in tumor therapy.

    Cerebellar Development

    While target derived neurotrophins are required for the survival of developing neurons in the peripheral nervous system, the functions of neurotrophins in the central nervous system have been unclear. Mice with a targeted gene deletion of brain-derived neurotrophic factor (BDNF) exhibit a wide based gait, and a defect in cerebellar foliation pattern. At the cellular level cerebellar granule cell survival and migration are both impaired in mutant animals. However, there is an increase in granule cell proliferation in mutants. These data suggest that BDNF acts as an autocrine/paracrine factor to regulate survival, migration, and differentiation of developming CNS neurons, and thereby affects neural patterning.

    Select Publications

    • Watson FL, Heerssen HM, Bhattacharyya A, Klesse L, Lin MZ, Segal RA. Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat Neurosci. 2001;4:981-8.
    • Rubin JB, Choi Y, Segal RA. Cerebellar proteoglycans regulate sonic hedgehog responses during development. Development. 2002;129:2223-32.
    • Borghesani PR, Peyrin JM, Klein R, Rubin J, Carter AR, Schwartz PM, Luster A, Corfas G, Segal RA. BDNF stimulates migration of cerebellar granule cells. Development. 2002;129:1435-42.
    • Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, Schmidt K, Kieran MW, Luster AD, Segal RA. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci U S A. 2003;100:13513-8. PMCID: PMC263845.
    • Heerssen HM, Pazyra MF, Segal RA. Dynein motors transport activated Trks to promote survival of target-dependent neurons. Nat Neurosci. 2004;7:596-604.
    • Choi Y, Borghesani PR, Chan JA, Segal RA. Migration from a mitogenic niche promotes cell-cycle exit. J Neurosci. 2005;25:10437-45.
    • Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME, Segal RA. Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron. 2007;55:53-68. PMCID: PMC2661852.
    • Pazyra-Murphy MF, Segal RA. Preparation and maintenance of dorsal root ganglia neurons in compartmented cultures. J Vis Exp. 2008;(20). pii: 951. doi: 10.3791/951. PMCID: PMC2731707.
    • Ha J, Lo KW, Myers KR, Carr TM, Humsi MK, Rasoul BA, Segal RA, Pfister KK. A neuron-specific cytoplasmic dynein isoform preferentially transports TrkB signaling endosomes. J Cell Biol. 2008;181:1027-39. PMCID: PMC2426944.
    • Cosker KE, Courchesne SL, Segal RA. Action in the axon: generation and transport of signaling endosomes. Curr Opin Neurobiol. 2008;18:270-5. PMCID: PMC2693191.
    • Pazyra-Murphy MF, Hans A, Courchesne SL, Karch C, Cosker KE, Heerssen HM, Watson FL, Kim T, Greenberg ME, Segal RA. A retrograde neuronal survival response: target-derived neurotrophins regulate MEF2D and bcl-w. J Neurosci. 2009;29:6700-9. PMCID: PMC2709981.
    • Chan JA, Balasubramanian S, Witt RM, Nazemi KJ, Choi Y, Pazyra-Murphy MF, Walsh CO, Thompson M, Segal RA. Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses. Nat Neurosci. 2009;12:409-17. PMCID: PMC2676236.
    • Courchesne SL, Karch C, Pazyra-Murphy MF, Segal RA.  Sensory Neuropathy Attributable to Loss of Bcl-w.  2011.  J Neurosci. 2011;31(5):1624-34. PMCID: PMC3074348
    • Courchesne SL, Pazyra-Murphy MF, Segal RA. Neuromuscular junction defects in mice with mutation of dynein heavy chain 1.  PLoS One. 2011;6(2):e16753. PMCID: PMC3035627
    • Zhou PC, Alfaro J, Chang EH, Zhao X, Porcionatto M, Segal RA. Numb links extracellular cues to intracellular polarity machinery to promote chemotaxis.  Dev Cell. 2011;20(5):610-22. PMCID: PMC3103748
    • Fainzilber M, Budnik V, Segal RA, Kreutz MR. From synapse to nucleus and back again- communication over distance within neurons. J Neurosci. 2011 Nov 9;31(45):16045-8.
    • Cosker KE, Pazyra-Murphy MF, Fenstermacher SJ, Segal RA. Target-derived neurotrophins coordinate transcription and transport of bclw to prevent axonal degeneration. J Neurosci. 2013 33(12):5195-207.

    Investigators

    • Zhou, Pengcheng, PhD

    Trainees

    • Cosker, Katharina, PhD
    • Gruber-Olipitz, Mariella, MD, PhD
    • Eisner, Adriana, BA
    • Fenstermacher, Sara, BA
    • Ekaterina, Pak, BS
    • Pease, Sarah, BS, BA
    • Yang, David, PhD
    • Zhou, Pengcheng, PhD
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