Rosalind Segal, M.D., PH.D.
Professor of Neurobiology
Our lab is interested in mechanisms whereby extracellular stimuli regulate proliferation and survival in the developing nervous system.
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.
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.
New progenitors NESTIN(g) in the EGL. November 22, 2013. Nature neuroscience.
Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities. September 29, 2013. Nature medicine.
Heparan Sulfate Proteoglycans Containing a Glypican 5 Core and 2-O-Sulfo-iduronic Acid Function as Sonic Hedgehog Co-receptors to Promote Proliferation. July 18, 2013. The Journal of biological chemistry.
Target-derived neurotrophins coordinate transcription and transport of bclw to prevent axonal degeneration. March 20, 2013. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Avanafil for the treatment of erectile dysfunction. January 1, 2012. Drugs of today (Barcelona, Spain : 1998).
From synapse to nucleus and back again--communication over distance within neurons. November 9, 2011. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Numb links extracellular cues to intracellular polarity machinery to promote chemotaxis. May 17, 2011. Developmental cell.
Neuromuscular junction defects in mice with mutation of dynein heavy chain 1. February 4, 2011. PloS one.
Sensory neuropathy attributable to loss of Bcl-w. February 2, 2011. The Journal of neuroscience : the official journal of the Society for Neuroscience.
The longer U(T)R, the further you go. March 1, 2010. Nature neuroscience.
Live or let die: CCM2 provides the link. September 10, 2009. Neuron.
A retrograde neuronal survival response: target-derived neurotrophins regulate MEF2D and bcl-w. May 20, 2009. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. May 1, 2009. Developmental cell.
Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses. March 15, 2009. Nature neuroscience.
Olfactory behavioral testing in the adult mouse. January 28, 2009. Journal of visualized experiments : JoVE.
Proteoglycan interactions with Sonic Hedgehog are selectively required for mitogenic responses January 1, 2009. Nature Neuroscience.
Preparation and maintenance of dorsal root ganglia neurons in compartmented cultures. October 17, 2008. Journal of visualized experiments : JoVE.
A neuron-specific cytoplasmic dynein isoform preferentially transports TrkB signaling endosomes. June 16, 2008. The Journal of cell biology.
Action in the axon: generation and transport of signaling endosomes. June 1, 2008. Current opinion in neurobiology.
Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. July 5, 2007. Neuron.
CXCR4 inhibition synergizes with cytotoxic chemotherapy in gliomas. November 15, 2006. Clinical cancer research : an official journal of the American Association for Cancer Research.
Migration from a mitogenic niche promotes cell-cycle exit. November 9, 2005. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Subtracting the Math: prominin-positive cerebellar stem cells in white matter. June 1, 2005. Nature neuroscience.
Dynein motors transport activated Trks to promote survival of target-dependent neurons. May 2, 2004. Nature neuroscience.
Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice. November 1, 2003. Developmental biology.
A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. October 31, 2003. Proceedings of the National Academy of Sciences of the United States of America.
Selectivity in neurotrophin signaling: theme and variations. February 18, 2003. Annual review of neuroscience.
Modulation of autoreactive responses of peripheral blood lymphocytes of patients with systemic lupus erythematosus by peptides based on human and murine anti-DNA autoantibodies. February 1, 2003. Clinical and experimental immunology.
Growth, survival and migration: the Trk to cancer. January 1, 2003. Cancer treatment and research.
Regional expression of p75NTR contributes to neurotrophin regulation of cerebellar patterning. January 1, 2003. Molecular and cellular neurosciences.
P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. October 20, 2002. Nature.
Medulloblastomas and primitive neuroectodermal tumors rarely contain polyomavirus DNA sequences. July 1, 2002. Neuro-oncology.
High-resolution imaging demonstrates dynein-based vesicular transport of activated Trk receptors. June 15, 2002. Journal of neurobiology.
Retrograde neurotrophin signaling: Trk-ing along the axon. June 1, 2002. Current opinion in neurobiology.
Cerebellar proteoglycans regulate sonic hedgehog responses during development. May 1, 2002. Development (Cambridge, England).
BDNF stimulates migration of cerebellar granule cells. March 1, 2002. Development (Cambridge, England).
Location, location, location: a spatial view of neurotrophin signal transduction. March 1, 2002. Trends in neurosciences.
Brain-derived neurotrophic factor modulates cerebellar plasticity and synaptic ultrastructure. February 15, 2002. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. October 1, 2001. Nature neuroscience.
Changing patterns of presentations of patients with HIV-related disease at a tertiary referral centre and its implications for physician training. July 1, 2001. International journal of STD & AIDS.
SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. June 1, 2001. Development (Cambridge, England).
Neurotrophins: which way did they go? May 29, 2001. Science's STKE : signal transduction knowledge environment.
Generation and utilization of phosphorylation state-specific antibodies to investigate signaling pathways. May 1, 2001. Current protocols in neuroscience / editorial board, Jacqueline N. Crawley ... [et al.].
Rett syndrome model suggests MECP2 gives neurons the quiet they need to think. April 1, 2001. Nature neuroscience.
Sustained signaling by phospholipase C-gamma mediates nerve growth factor-triggered gene expression. April 1, 2001. Molecular and cellular biology.
Suppression of experimental systemic lupus erythematosus (SLE) in mice via TNF inhibition by an anti-TNFalpha monoclonal antibody and by pentoxiphylline. January 1, 2001. Lupus.
Sustained signaling by PLCgamma mediates NGF-triggered gene expression January 1, 2001. Mol Cell Bio.
Skeletal muscle deformity and neuronal disorder in Trio exchange factor-deficient mouse embryos. October 24, 2000. Proceedings of the National Academy of Sciences of the United States of America.
Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. August 1, 2000. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Immune response of SLE patients to peptides based on the complementarity determining regions of a pathogenic anti-DNA monoclonal antibody. May 1, 2000. Journal of clinical immunology.
Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. March 28, 2000. Proceedings of the National Academy of Sciences of the United States of America.
Effect of aging on cytokine production in normal and experimental systemic lupus erythematosus-afflicted mice. March 1, 2000. Experimental gerontology.
Rapid nuclear responses to target-derived neurotrophins require retrograde transport of ligand-receptor complex. September 15, 1999. The Journal of neuroscience : the official journal of the Society for Neuroscience.
TrkA glycosylation regulates receptor localization and activity. May 1, 1999. Journal of neurobiology.
Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. February 1, 1999. Cancer research.
Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. August 4, 1998. Proceedings of the National Academy of Sciences of the United States of America.
Cerebellar pathology in BDNF -/- mice: the classic view of neurotrophins is changing. March 1, 1998. Molecular psychiatry.
Neurotrophins in cerebellar granule cell development and medulloblastoma. December 1, 1997. Journal of neuro-oncology.
Trk receptors function as rapid retrograde signal carriers in the adult nervous system. September 15, 1997. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Abnormal cerebellar development and foliation in BDNF-/- mice reveals a role for neurotrophins in CNS patterning. August 1, 1997. Neuron.
Blockade of endogenous ligands of trkB inhibits formation of ocular dominance columns. July 1, 1997. Neuron.
Cytokine manipulation by methotrexate treatment in murine experimental systemic lupus erythematosus. June 1, 1997. The Journal of rheumatology.
Effect of aging on cytokine production in normal and experimental systemic lupus erythematosus afflicted mice. June 1, 1997. Mechanisms of ageing and development.
Kinetics of cytokine production in experimental systemic lupus erythematosus: involvement of T helper cell 1/T helper cell 2-type cytokines in disease. March 15, 1997. Journal of immunology (Baltimore, Md. : 1950).
Regulation of neuronal survival by the serine-threonine protein kinase Akt. January 31, 1997. Science (New York, N.Y.).
Hereditary ataxia with sensory neuronopathy: Biemond's ataxia. January 1, 1997. Neurology.
Neurotrophins and programmed cell death during cerebellar development. January 1, 1997. Advances in neurology.
Development of the Nervous System January 1, 1997. Neonatal and Fetal Medicine, Poland RA and Fox WW, eds..
Differential utilization of Trk autophosphorylation sites. August 16, 1996. The Journal of biological chemistry.
Modulation of experimental systemic lupus erythematosus. January 1, 1996. Israel journal of medical sciences.
Intracellular signaling pathways activated by neurotrophic factors. January 1, 1996. Annual review of neuroscience.
Methotrexate treatment in murine experimental systemic lupus erythematosus (SLE); clinical benefits associated with cytokine manipulation. July 1, 1995. Clinical and experimental immunology.
Axonal growth and fasciculation linked to differential expression of BDNF and NT3 receptors in developing cerebellar granule cells. July 1, 1995. The Journal of neuroscience : the official journal of the Society for Neuroscience.
Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. December 20, 1994. Proceedings of the National Academy of Sciences of the United States of America.
Inhibition of autoantibody production in experimental SLE by pre-immunization with DNA. January 1, 1994. Autoimmunity.
Changes in neurotrophin responsiveness during the development of cerebellar granule neurons. December 1, 1992. Neuron.
The influence of aging on the induction and manifestations of experimental systemic lupus erythematosus. September 1, 1992. Journal of clinical immunology.
Induction of experimental systemic lupus erythematosus (SLE) in mice with severe combined immunodeficiency (SCID). August 1, 1992. Clinical and experimental immunology.
Monozygotic twins with seizures. Shared characteristics. October 1, 1991. Archives of neurology.
Assessment and treatment of a pediatric patient in chronic care: ethnographic methods applied to occupational therapy practice. March 1, 1991. The American journal of occupational therapy : official publication of the American Occupational Therapy Association.
Anti-DNA idiotype- and anti-idiotype-specific T cell responses in patients with systemic lupus erythematosus and their first-degree relatives. December 1, 1990. Clinical and experimental immunology.
In vitro T-cell functions specific to an anti-DNA idiotype and serological markers in patients with systemic lupus erythematosus (SLE). May 1, 1988. Journal of clinical immunology.
Subarachnoid hemorrhage and the heart. January 1, 1986. Neurosurgery.
Phosphorylation in isolated Chlamydomonas axonemes: a phosphoprotein may mediate the Ca2+-dependent photophobic response. November 1, 1985. The Journal of cell biology.
Mutant strains of Chlamydomonas reinhardtii that move backwards only. June 1, 1984. The Journal of cell biology.
Studies of fibronectin matrices in living cells with fluoresceinated gelatin. October 1, 1980. The Journal of cell biology.
Studies on intercellular LETS glycoprotein matrices. June 1, 1978. Cell.
Differences in the responsiveness of splenic, lymph node, and peripheral blood lymphoid cells to tumor membrane extracts. January 1, 1977. Cancer research.
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