Cell-cell Interactions2 In Cerebellar Development
Rosalind A Segal, Associate Professor
Dana-farber Cancer Institute 44 Binney St Boston, Ma 02115
Grant 5R01NS037757-09 from National Institute Of Neurological Disorders And Stroke IRG: MDCN
Abstract: During development of the nervous system, precursor cells divide in specialized proliferative zones, then migrate away from these zones and differentiate. The mechanisms that allow coordinated cell cycle exit and directed migration can readily be examined in the developing cerebellum. In studies supported by this grant, my colleagues and I identified two extracellular factors that regulate migration of cerebellar precursors stromal cell derived factor (SDF-1 alpha) and brain derived neurotrophic factor (BDNF). We demonstrated that mice with targeted gene deletions of either SDF-1alpha or of BDNF exhibit both aberrant migration and proliferation of neuronal precursors in the cerebellum. In the proposed studies we will define the mechanisms whereby these factors stimulate migration, and how they coordinately influence proliferation. 1. The first specific aim is to determine the mechanism by which BDNF promotes granule cell migration. We will use genetic and pharmacologic tools to identify the signal transduction pathways required for directed migration, focusing on the possibility that TrkB activity stimulates PI3 kinase to promote cell migration. 2. The second specific aim is to test the hypothesis that a gradient of BDNF causes redistribution of TrkB receptors to amplify the gradient and provide a direction for chemotaxis. Preliminary data indicate that BDNF induces an asymmetric distribution of the BDNF receptor, TrkB, with accumulation of receptors at the leading edge. We will test the hypothesis that redistribution of TrkB receptors allows amplification of the gradient, determine whether TrkB redistribution reflects movement of surface receptors or the addition of new receptors to the surface, and determine whether receptor redistribution is needed for chemotaxis. 3. The third specific aim is to test the hypothesis that SDF-1alpha functions as a spatially restricted competence factor that limits SHH-induced proliferation to the EGL. We will investigate the possibility that SHH and SDF function as competence and progression factors for precursor proliferation, and identify transcriptional targets that depend on the synergy of these two factors Taken together, these studies will identify mechanisms that regulate the directed migration of granule cells, and define the relationship between migration and proliferation. Since unregulated migration and proliferation are the hallmarks of malignancy, these studies will provide a basis for understanding and treating brain tumors.
Keywords: brain derived neurotrophic factor, cell cell interaction, cell growth regulation, cell migration, cell proliferation, cerebellar Purkinje cell, granule cell, biological signal transduction, enzyme induction /repression, growth factor receptor, phosphatidylinositol 3 kinase, phosphorylation, protein tyrosine kinase, synapse, confocal scanning microscopy, green fluorescent protein, immunocytochemistry, laboratory mouse, laboratory rat, nervous system transplantation, tissue /cell culture
Project start date: 1998-09-30
Project end date: 2008-03-31
5R01NS037757-09 (2006): $317265
Sponsored Links Excellgen http://Excellgen.com
CELL-CELL INTERACTIONS IN CEREBELLAR DEVELOPMENT
Rosalind A Segal, Professor Of Neurobiology
Dana-farber Cancer Institute, 44 Binney St, Boston, Ma 02115
Grant 5R01NS037757-11 from National Institute Of Neurological Disorders And Stroke
Abstract: Segal, Rosalind A. 2 R01 NS037757-10A2
Keywords: Acute; Animals; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; BDGF; BDNF; BDNF Receptor; BDNF/NT-3 Growth Factors Receptor; Binding; Binding (Molecular Function); Brain; Brain Neoplasia; Brain Neoplasms; Brain Tumors; Brain-Derived Neurotrophic Factor; Cell Communication; Cell Communication and Signaling; Cell Interaction; Cell Polarity; Cell Signaling; Cell-to-Cell Interaction; Cells; Cerebellum; Chemoattractants; Chemotactic Factors; Chemotaxins; Chemotaxis; Complex; Cues; Defect; Development; Disease; Disorder; Distal; Dyslexia; Encephalon; Encephalons; Endocytosis; Endosomes; Family; GFAC; GP145-TRKB; Grant; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; IGL; IGL@ gene cluster; Immigrations; Immunoglobulin Lambda Gene; Immunoglobulin Lambda Locus; In Vitro; In-Migration; Intracellular Communication and Signaling; Investigation; Kanner`s Syndrome; Lambda Light Chain Gene; Lead; Location; M Phase; M phase (cell cycle); MGC34632; Maintenance; Maintenances; Malignant; Malignant - descriptor; Mitosis; Mitosis Stage; Mitotic; Modeling; Molecular; Molecular Interaction; NTRK2; NTRK2 Receptor; Nervous System, Brain; Neural Development; Neural Stem Cell; Neurotrophic Factor, Brain-Derived, Receptor; Neurotrophic Tyrosine Kinase Receptor Type 2; Pb element; Phase; Population; Process; Proteins; Public Health; Radial; Receptor, trkB; Receptosomes; Research; Role; Signal Transduction; Signal Transduction Systems; Signaling; Staging; TRKB; TRKB Tyrosine Kinase; Testing; Time; Tumor Cell; VESCL; Vesicle; Word Blindness; Work; biological signal transduction; brain cell; brain growth promoting activity; brain trophin; brain-derived growth factor; cellular polarity; complement chemotactic factor; d-Numb; daughter cell; disease/disorder; extracellular; gene product; granule cell; heavy metal Pb; heavy metal lead; in vivo; migration; mutant; neoplastic cell; nerve stem cell; neural progenitor cells; neurodevelopment; neuronal progenitor; neuronal progenitor cells; neuropsychiatric; neuropsychiatry; numb protein; precursor cell; public health medicine (field); response; social role; synapse formation; synaptogenesis; trafficking; trkB(gp145) Protein; tumors in the brain
Relevance: Relevancy to Public Health The proposed studies will investigate how growth factors induce directed migration of neural precursors. These investigations of polarity and migration will lead to approaches for restricting the extensive migration of malignant brain tumor cells that arise from neural precursors. In addition these studies will explain why errors in migration predispose to defects in brain circuitry in neuropsychiatric disorders such as dyslexia and autism
Project start date: 1998-09-30
Project end date: 2011-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-07-070
5R01NS037757-11 (2010): $409058
CELL/CELL INTERACTIONS IN CEREBELLAR DEVELOPMENT
Rosalind A Segal, Associate Professor
Dana-farber Cancer Institute
44 Binney St
boston, Ma 02115
Grant 5R01NS037757-05 from National Institute Of Neurological Disorders And Stroke IRG: NEUB
Abstract: Purkinje cells are the sole output from the cerebellar cortex, and so diseases that alter Purkinje cell develop and function have devastating effects on balance and coordination. My colleagues and I have demonstrated that the neurotrophin, BDNF, is necessary for normal Purkinje cell development, particularly for dendritic arborization. In the proposed research we will identify the cells that synthesize BDNF to regulate Purkinje cell development and determine whether the p75 receptor plays a role in this regulation. We will investigate further the nature of the biological effects of BDNF on Purkinje cells, to determine whether BDNF regulates Purkinje cell synapses. Specific aim 1 is to test the hypothesis that BDNF synthesized and released by granule cell acts in an anterograde fashion to regulated Purkinje cell development; we will also examine the alternative possibilities that BDNF is instead involved in the interactions of climbing fiber or deep cerebellar nuclei neurons with Purkinje cells. We will use genetic or mechanical means to remove granule cells in vivo or remove afferent connections to the cerebellar cortex, and determine whether Purkinje still accumulate BDNF and undergo Trk phosphorylation. We will use organotypic and dissociated cell cultures to determine whether BDNF is required for granule cells to regulate Purkinje cell dendritic arborization. Specific aim 2 is to test the hypothesis that both TrkB and the p75 receptor mediate the effects of BDNF in developing Purkinje cells. While our previous work has demonstrated that activation of the TrkB receptor is a critical component in the Purkinje cell response to BDNF, others have shown that antibodies to p75 perturb Purkinje cell dendritic growth and survival, suggesting that both receptors may participate in the BDNF response. We will analyze Purkinje cell morphology, cerebellar foliation, Trk phosphorylation and BDNF uptake in p75/BDNF compound mutant mice. These experiments will indicate signal transduction pathways critical for regulating Purkinje cell development. Specific aim 3 is to test the hypothesis that BDNF is involve din the formation and maturation of granule cell-Purkinje cell synapses. We will use structural, biochemical and electrophysiologic approaches to compare parallel fiber Purkinje cell synapses in wild type and BDNF-/- mice, and to evaluate acute and chronic effects of BDNF on Purkinje cell synapses. These studies will identify extracellular factors that regulate Purkinje cell development, and could provide the basis for therapeutic applications of neurotrophic factors on drugs in treating cerebellar diseases
Keywords: cell cell interaction, cell growth regulation, cerebellar Purkinje cell, granule cell, neurotrophic factor biological signal transduction, growth factor receptor, phosphorylation, synapse immunocytochemistry, laboratory mouse, nervous system transplantation, tissue /cell culture
Project start date: 1998-09-30
Project end date: 2003-02-28
5R01NS037757-05 (2001): $241414
5R01NS037757-04 (2000): $234422
5R01NS037757-03 (1999): $227640
Cell-cell Interactions2 In Cerebellar Development
Rosalind A Segal, Associate Professor
Dana-farber Cancer Institute 44 Binney St Boston, Ma 02115
Grant 5R01NS037757-08 from National Institute Of Neurological Disorders And Stroke IRG: MDCN
Abstract: During development of the nervous system, precursor cells divide in specialized proliferative zones, then migrate away from these zones and differentiate. The mechanisms that allow coordinated cell cycle exit and directed migration can readily be examined in the developing cerebellum. In studies supported by this grant, my colleagues and I identified two extracellular factors that regulate migration of cerebellar precursors stromal cell derived factor (SDF-1 alpha) and brain derived neurotrophic factor (BDNF). We demonstrated that mice with targeted gene deletions of either SDF-1alpha or of BDNF exhibit both aberrant migration and proliferation of neuronal precursors in the cerebellum. In the proposed studies we will define the mechanisms whereby these factors stimulate migration, and how they coordinately influence proliferation. 1. The first specific aim is to determine the mechanism by which BDNF promotes granule cell migration. We will use genetic and pharmacologic tools to identify the signal transduction pathways required for directed migration, focusing on the possibility that TrkB activity stimulates PI3 kinase to promote cell migration. 2. The second specific aim is to test the hypothesis that a gradient of BDNF causes redistribution of TrkB receptors to amplify the gradient and provide a direction for chemotaxis. Preliminary data indicate that BDNF induces an asymmetric distribution of the BDNF receptor, TrkB, with accumulation of receptors at the leading edge. We will test the hypothesis that redistribution of TrkB receptors allows amplification of the gradient, determine whether TrkB redistribution reflects movement of surface receptors or the addition of new receptors to the surface, and determine whether receptor redistribution is needed for chemotaxis. 3. The third specific aim is to test the hypothesis that SDF-1alpha functions as a spatially restricted competence factor that limits SHH-induced proliferation to the EGL. We will investigate the possibility that SHH and SDF function as competence and progression factors for precursor proliferation, and identify transcriptional targets that depend on the synergy of these two factors Taken together, these studies will identify mechanisms that regulate the directed migration of granule cells, and define the relationship between migration and proliferation. Since unregulated migration and proliferation are the hallmarks of malignancy, these studies will provide a basis for understanding and treating brain tumors.
Keywords: brain derived neurotrophic factor, cell cell interaction, cell growth regulation, cell migration, cell proliferation, cerebellar Purkinje cell, granule cell, biological signal transduction, enzyme induction /repression, growth factor receptor, phosphatidylinositol 3 kinase, phosphorylation, protein tyrosine kinase, synapse, confocal scanning microscopy, green fluorescent protein, immunocytochemistry, laboratory mouse, laboratory rat, nervous system transplantation, tissue /cell culture
Project start date: 1998-09-30
Project end date: 2007-03-31
5R01NS037757-08 (2005): $324900
5R01NS037757-07 (2004): $324900
Grants awarded to Rosalind A Segal
RETROGRADE SIGNAL TRANSDUCTION BY NEUROTROPHINS
Rosalind A Segal, Associate Professor
Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215
Grant 5R01NS035148-03 from National Institute Of Neurological Disorders And Stroke IRG: NEUC
Abstract: This grant addresses an anatomical problem in signal transduction that is unique to nerve cells. How do target-derived growth factors regulate events in the nerve cell body following presentation to nerve endings that can be meters away from that ultimate target? Conventional growth factor signal transduction pathways would seem inadequate to the challenge without special adaptations. Retrograde transport, though well documented for neurotrophins, is not a proven component of the signal transduction process. The goal of this research is to learn how target-derived neurotrophins transmit information through nerve axons. A key to our study plan is a panel of activation state-specific antibodies we ve raised to high affinity neurotrophin receptors (Trks). These antibodies resolve and report both catalytic and signaling functions of Trks in vivo. We will draw upon the sensitivity and specificity of these antibodies to study signal transduction by focal sources of BDNF in two complementary systems - sciatic nerve, and cerebellar granule neurons grown in a compartmented culture system (Campenot chambers). Sciatic nerve axons are long enough to clearly separate the target, axon and cell body. Granule cells, which can be readily purified in large numbers, express high levels of the BDNF receptor Trk B and so are ideal for certain mechanistic studies. We ve done extensive preliminary work on both of these BDNF-responsive nerve cell systems. We have shown that a holus of BDNF at nerve endings leads to phosphorylation of Trk B within axons - that the phosphate is at a functional tyrosine (the SHC binding site) - that the change in Trk B phosphorylation state propagates through the axon towards the cell body- and that it travels at a rate of at least 60 mm/hr. This rate of signal propagation is roughly five times faster than conventional retrograde vesicular transport and it raises the possibility that other mechanisms are involved in target derived signal transduction. Our study plan builds upon these preliminary observations. We have three objectives. Objective one is to determine whether phospho Trk B executes either of its two known functions while in transit through the axon. Bearing in mind that activated Trk B is both a tyrosine kinase and a "platform" for assembly of the signal generating particle, our specific aims are to learn; i. whether phospho Trk B in the axons is catalytically active and ii. whether it is associated with signal generating proteins SHC, PLC- gamma and PI3 kinase. Objective two is to determine how the Trk B phosphorylation state changes propagate so quickly through the axon. Specific aims are to learn; i. whether we are observing the transport of phospho Trk B itself; ii. whether propagation of the phospho Trk B signal is linked to retrograde vesicular transport. Objective three is to learn how phospho Trk B transduces a signal at the neuronal cell body. Specific aims are to learn whether; i. the Ras/Raf signal generating apparatus is activated; ii, MAP kinase is activated and relocated into the nucleus and iii. immediate early genes are induced in response to BDNF.
Keywords: mitogen activated protein kinase, neuronal transport, neurotrophic factor, protein transport, protein tyrosine kinase, antiserum, cerebellum, colchicine, enzyme activity, gene induction /repression, granule cell, inositol phosphate, neuropharmacology, phosphatidylinositol 3 kinase, phospholipase C, phosphoprotein, regulatory gene, sciatic nerve, transcription factor, confocal scanning microscopy, gel mobility shift assay, immunoprecipitation, laboratory mouse, laboratory rat, tissue /cell culture
Project start date: 1996-05-01
Project end date: 1998-10-31
5R01NS035148-03 (1998): $344211
5R01NS035148-02 (1997): $330971
DIFFERENTIATION MECHANISMS IN RETINAL STEM CELLS
Rosalind A Segal, Associate Professor
Beth Israel Deaconess Medical Center
330 Brookline Avenue, Br 264
boston, Ma 02215
Grant 5K08NS001488-06 from National Institute Of Neurological Disorders And Stroke IRG: NST
Abstract: The proposed research is to define the multipotential retinal precursor cell and mechanisms which regulate the fate choices of this cell into mature neurons and glia. Elucidating this differentiation pathway is important for understanding congenital syndromes of dysgenetic brains, neurogenic tumors and neurodegenerative diseases. The newly identified intermediate filament protein nestin appears to be specific for neuronal and glial precursor cells in many areas of the CNS. The expression of nestin in retinal stem cells will be determined . Once the pathway from a nestin-positive precursor to a mature retinal cell has been delineated in vivo and in vitro, retinal precursor cell lines will be generated and characterized. These cell lines will provide an in vitro system for studying neuronal differentiation. Growth factors, substrates and cell-cell contacts important for guiding the differentiation of neuronal cell will be investigated using these new cell lines
Keywords: cell differentiation, cell growth regulation, developmental neurobiology, gene expression, retina, retinal ganglion antigen, biomarker, cell cell interaction, cell cycle, clone cell, fibroblast growth factor, oncogene embryo /fetus, immunocytochemistry, laboratory rat, microinjection, monoclonal antibody, staining, tissue /cell culture, transgenic animal
Project start date: 1991-02-01
Project end date: 1996-06-30
5K08NS001488-06 (1994): $89181
5K08NS001488-04 (1993): $89100
SPATIAL CONSIDERATIONS IN NEURONAL SURVIVAL SIGNALS
Rosalind A Segal, Professor Of Neurobiology
Dana-farber Cancer Institute, 44 Binney St, Boston, Ma 02115
Grant 5R01NS050674-05 from National Institute Of Neurological Disorders And Stroke
Abstract: The neurodegenerative disease amyotrophic lateral sclerosis (ALS) can be caused by mutations in components of the intracellular motor protein dynein [1]. What, then, are the critical molecules transported by dyneins that are essential for neuronal survival? My colleagues and I have shown that dynein-based transport is required for survival of neurons that depend on target-derived neurotrophic factors. We have shown that this reflects the role of axonal dynein in mediating transport of activated neurotrophin receptors (Trks) within large signaling endosomes. Therefore, we hypothesize that ALS may result from deficiencies in long-range neurotrophic factor signaling, and that restoring these retrograde signals will provide an effective therapeutic approach to the disease. We have identified a set of genes that are preferentially induced by neurotrophin stimulation of distal axons (retrograde signals) rather than by stimulation of cell bodies . (anterograde signals), a set that we designate as retrograde response genes. The retrograde response gene set contains several members that are likely to protect cells from progressive neurodegeneration, including the anti-apoptotic gene bclw and the survival-promoting factor IGF-1. In the proposed studies we will build on our identification of spatially selective neurotrophin responses to determine the mechanisms and functions of specialized retrograde signals. We have three aims. 1. To determine the mechanisms responsible for induction of retrograde response genes by target-derived , neurotrophins, using both motor and sensory neurons grown in compartmented cultures. 2. To determine the functions of retrograde response genes in developing and mature neurons. We will focus on bclw, a poorly understood pro-survival bc!2 family member that is preferentially expressed in the mature nervous system, and can protect diverse neurons from apoptotic stimuli. 3. To test the hypothesis that mutations in dynein that cause ALS do so by interfering with the signaling pathways that induce bclw and other retrograde response genes. We will determine whether expression of these genes protects motor neurons from progressive degeneration. Understanding the mechanism and significance of long distance survival pathways may lead to new therapeutic approaches for ALS and other devastating neurodegenerative disorders
Keywords: ALS; Address; Adenosine Triphosphatase, Dynein; Afferent Neurons; Amyotrophic Lateral Sclerosis; Apoptotic; Axon; Axonal Transport; Axoplasmic Transport; Bears; Cell Body; Cell Communication and Signaling; Cell Signaling; Cells; Characteristics; Culture Techniques; Data; Degenerative Diseases, Nervous System; Degenerative Disorder; Degenerative Neurologic Disorders; Dendrites; Development; Disease; Disease Progression; Disorder; Distal; Doctor of Medicine; Doctor of Philosophy; Dynein; Dynein ATPase; Dynein Adenosinetriphosphatase; EC 2.7; EC 2.7.2-; Endosomes; Extracellular Signal-Regulated Kinases; Family member; Gehrig`s Disease; Gene Expression; Gene Targeting; Genes; Genetic Alteration; Genetic Change; Genetic defect; Goals; IGF-1; IGF-I; IGF-I-SmC; IGF1; In Vitro; Insulin-Like Growth Factor 1; Insulin-Like Growth Factor I; Insulin-Like Somatomedin Peptide I; Intervention; Intervention Strategies; Intracellular Communication and Signaling; Investigators; Kinases; Lead; Lou Gehrig Disease; M.D.; MAP kinase; MAPK; Mammals, Mice; Mediating; Mice; Mitogen-Activated Protein Kinases; Motor; Motor Cell; Motor Neuron Disease, Amyotrophic Lateral Sclerosis; Motor Neurons; Murine; Mus; Mutation; NRVS-SYS; Natural regeneration; Nerve Cells; Nerve Degeneration; Nerve Growth Factor Receptors; Nerve Unit; Nervous System; Nervous system structure; Neural Cell; Neurocyte; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic Body System; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neurologic Organ System; Neuron Degeneration; Neurons; Neurons, Afferent; Neurons, Sensory; Neurotrophic Factor Receptor; Pathway interactions; Pb element; Ph.D.; PhD; Phosphotransferases; Process; Programs (PT); Programs [Publication Type]; Proteins; Receptors, NGF; Receptors, Nerve Growth Factor; Receptors, Neurotrophin; Receptosomes; Regeneration; Research Personnel; Researchers; Role; Sensory Cell Afferent Neuron; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Somatomedin C; Staging; Stimulus; Targetings, Gene; Testing; Therapeutic; Time; Transphosphorylases; Ursidae; Ursidae Family; base; biological signal transduction; cell body (neuron); cohort; degenerative condition; degenerative disease; disease/disorder; dynein ATP phosphohydrolase (tubulin translocating); gene induction; gene product; genome mutation; heavy metal Pb; heavy metal lead; in vivo; interventional strategy; member; motoneuron; neural cell body; neural degeneration; neurodegeneration; neurodegenerative illness; neuronal; neuronal cell body; neuronal degeneration; neuronal survival; neurotrophic factor; neurotrophin; neutrophin; novel therapeutic intervention; pathway; presynaptic; programs; progressive neurodegeneration; regenerate; response; social role; soma; transcription factor
Project start date: 2005-08-15
Project end date: 2010-04-30
Budget start date: 1-MAY-2009
Budget end date: 30-APR-2010
5R01NS050674-05 (2009): $374947
5R01NS050674-03 (2007): $374947
5R01NS050674-02 (2006): $389040
1R01NS050674-01A1 (2005): $393125
RETROGRADE SIGNALING BY NEUROTROPHINS
Rosalind A Segal, Associate Professor
Dana-farber Cancer Institute 44 Binney St Boston, Ma 02115
Grant 5R01NS035148-08 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: Target derived neurotrophins regulate neuronal survival and function. Little is known about the mechanisms by which neurotrophins regulate events in the nerve cell body when presented to nerve ending that may be as far as a meter away. Previously, we have shown that neurotrophin receptors (Trks) themselves serve as rapid retrograde signal carriers in rat sciatic nerve axons. The research described here builds upon this work. We have three specific aims Aim one is to learn how Trks function as retrograde signal carriers. Our preliminary data suggest that a specialized vesicular transport process is utilized to convey Trk signal generating particles in the retrograde direction. To test this hypothesis, activation state-specific antibodies will be used as immuno-electron microscopy reagents and as immunoaffinity reagents to localize and isolate the Trk signal carrying complex in rat sciatic nerve axons. Temperature sensitive mutations of dynamin will be expressed in compartmented cultures of DRG neurons to evaluate the role of receptor internalization in retrograde signaling. Retrograde movement of activated Trks will be visualized in living DRG neurons using Green Fluorescent Protein tags. Aim two is to learn how P-Trk signal arriving at the nerve cell body is converted to a nuclear signal. Our preliminary data suggest that Trk signal arriving from a remote source of stimulation (the nerve ending) is processed by ERK isoforms distinct from the ones that process Trk signal from a local source (the cell body). We will use genetic and biochemical approaches to identify ERKs that are activated by retrograde signal and evaluate their role(s) in nuclear responses. Aim three opens a new avenue of inquiry. Our preliminary data suggest that PI3 kinase activity is required for nuclear responses to remote, but not local, neurotrophin stimulation. PI3 kinases are known to regulate membrane trafficking. In addition, phospholipid products of PI3 kinases serve as activators for serine/threonine protein kinases such as Akt. Genetic and biochemical approaches will be used to test the hypothesis that one or both of these PI3 kinase functions are required for retrograde signaling through long axons. These studies will shed light on the molecular basis of neurodegenerative diseases, and provide guidelines for rational drug design and delivery in treating such disorders.
Keywords: axon, biological signal transduction, neuronal transport, neuropeptide receptor, neurotrophic factor, protein transport, vesicle /vacuole, dynamin, dynein ATPase, gene induction /repression, growth factor receptor, mitogen activated protein kinase, receptor mediated endocytosis, sciatic nerve, transcription factor, confocal scanning microscopy, green fluorescent protein, immunoaffinity chromatography, immunocytochemistry, immunoelectron microscopy, immunofluorescence technique, immunoprecipitation, laboratory rat, tissue /cell culture, transfection
Project start date: 1996-05-01
Project end date: 2003-04-30
5R01NS035148-08 (2002): $367456
5R01NS035148-07 (2001): $358629
Sponsored Links Excellgen http://Excellgen.com
5R01NS035148-06 (2000): $348228
2R01NS035148-05 (1999): $338085
CELL-CELL INTERACTIONS IN CEREBELLAR DEVELOPMENT
Rosalind A Segal, Professor Of Neurobiology
Dana-farber Cancer Institute, 44 Binney St, Boston, Ma 02115
Grant 2R01NS037757-10A2 from National Institute Of Neurological Disorders And Stroke
Abstract: Segal, Rosalind A. 2 R01 NS037757-10A2
Keywords: Acute; Animals; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; BDGF; BDNF; BDNF Receptor; BDNF/NT-3 Growth Factors Receptor; Binding; Binding (Molecular Function); Brain; Brain Neoplasia; Brain Neoplasms; Brain Tumors; Brain-Derived Neurotrophic Factor; Cell Communication; Cell Communication and Signaling; Cell Interaction; Cell Polarity; Cell Signaling; Cell-to-Cell Interaction; Cells; Cerebellum; Chemoattractants; Chemotactic Factors; Chemotaxins; Cues; Defect; Development; Disease; Disorder; Distal; Dyslexia; Encephalon; Encephalons; Endocytosis; Endosomes; Family; GP145-TRKB; Grant; IGL; IGL@ gene cluster; Immigrations; Immunoglobulin Lambda Gene; Immunoglobulin Lambda Locus; In Vitro; In-Migration; Intracellular Communication and Signaling; Kanner`s Syndrome; Lambda Light Chain Gene; Lead; Location; M Phase; M phase (cell cycle); MGC34632; Maintenance; Maintenances; Malignant; Malignant - descriptor; Mitosis; Mitosis Stage; Mitotic; Modeling; Molecular; Molecular Interaction; NTRK2; NTRK2 Receptor; Nervous System, Brain; Neural Development; Neurotrophic Factor, Brain-Derived, Receptor; Neurotrophic Tyrosine Kinase Receptor Type 2; Pb element; Phase; Population; Process; Protein Family; Proteins; Radial; Receptor, trkB; Receptosomes; Research; Role; Signal Transduction; Signal Transduction Systems; Signaling; Staging; Synapses; Synaptic; TRKB; TRKB Tyrosine Kinase; Testing; Time; Tumor Cell; VESCL; Vesicle; Word Blindness; Work; ing; biological signal transduction; brain cell; brain growth promoting activity; brain trophin; brain-derived growth factor; cellular polarity; complement chemotactic factor; d-Numb; daughter cell; disease/disorder; extracellular; gene product; granule cell; heavy metal Pb; heavy metal lead; in vivo; migration; mutant; neoplastic cell; neurodevelopment; neuropsychiatric; neuropsychiatry; numb protein; precursor cell; public health relevance; response; social role; synapse formation; synaptogenesis; trkB(gp145) Protein; tumors in the brain
Relevance: Segal, Rosalind A. 2 R01 NS037757-10A2
Project start date: 1998-09-30
Project end date: 2011-06-30
Budget start date: 16-JUL-2009
Budget end date: 30-JUN-2010
PFA/PA: PA-07-070
2R01NS037757-10A2 (2009): $404787
Rosalind A Segal
Dana-farber Cancer Institute, 44 Binney St, Boston, Ma 02115
Grant 5DP1OD000839-05 from National Cancer Institute
Abstract: Recent studies have focused attention on the role of mitogenic niches in regulating stem cell self?renewal, and have emphasized the importance of proteoglycans in forming such microenvironments. However, more than 50 years after the genetic code was deciphered, we do not know whether sugar chains on proteoglycans encode biologically important information. The potential complexity of such a ?glyco code? is enormous, but little is known about the features of the proteoglycans involved in mitogenic regulation, or the signaling mechanisms required for stem cell renewal. To decipher whether there is a glyco code we will identify proteoglycans that specify stem cell renewal in the mammalian brain. We will rely on a genetic approach to proteoglycan biology and on newly developing innovations in mass spectrometry that allow large scale analysis of the sugar composition of proteoglycans. We will generate mutated growth factors capable of binding to cognate receptors, but unable to bind proteoglycans. We will ascertain whether individual proteoglycans modulate the signaling pathway and the biological response elicited by a growth factor, perhaps by influencing the location, presentation, or oligomerization of the factor. We will begin by focusing on Sonic Hedgehog (Shh), which is mitogenic for stem cells in the cerebellum, cortex, and in diverse cancers. We will identify proteoglycans required for Shh- mediated proliferation using a new assay for mitogenic niches, and we will determine how a glyco code might regulate stem cell propagation. As the work progresses we will extend our studies to define proteoglycan structures that modulate the response of stem cells to additional agents such as EGF or FGF family members. These studies will contribute to the identification of a glyco-code, and will determine mechanisms that maintain ?stemness?. Such studies can lead to enhanced therapies for disorders from Alzheimers disease to cancers to stroke
Keywords: Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer`s; Alzheimer`s Disease; Alzheimers Dementia; Alzheimers disease; Apoplexy; Assay; Attention; Award; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological; Biological Assay; Biology; Brain; Cancers; Cell Communication and Signaling; Cell Signaling; Cerebellum; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Code; Coding System; DNA Synthesis Factor; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Disease; Disorder; ECGF; EGF; EGF gene; Encephalon; Encephalons; Endothelial Cell Growth Factor; Erinaceidae; FGF; Family member; Fibroblast Growth Factor; Fibroblast Growth Regulatory Factor; GFAC; Genetic; Genetic Code; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; HBGF; Hedgehogs; Individual; Intracellular Communication and Signaling; Lead; Location; Malignant Neoplasms; Malignant Tumor; Mass Spectrum; Mass Spectrum Analysis; Mediating; Molecular Interaction; Mother Cells; Mutate; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Pb element; Photometry/Spectrum Analysis, Mass; Primary Senile Degenerative Dementia; Progenitor Cells; Proteoglycan; Receptor Protein; Regulation; Role; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Specific qualifier value; Specified; Spectrometry, Mass; Spectroscopy, Mass; Spectrum Analyses, Mass; Spectrum Analysis, Mass; Stem cells; Stroke; Structure; URG; United States National Institutes of Health; Vascular Accident, Brain; Work; biological signal transduction; brain attack; cerebral vascular accident; dementia of the Alzheimer type; disease/disorder; heavy metal Pb; heavy metal lead; innovate; innovation; innovative; malignancy; neoplasm/cancer; primary degenerative dementia; receptor; response; self-renewal; senile dementia of the Alzheimer type; social role; stem cell division; stemness; stroke; sugar
Project start date: 2006-09-28
Project end date: 2011-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: RFA-RM-06-005
5DP1OD000839-05 (2010): $855000
5DP1OD000839-04 (2009): $855000
5DP1OD000839-03 (2008): $855000
5DP1OD000839-02 (2007): $855000
Rosalind A Segal, Associate Professor
Dana-farber Cancer Institute 44 Binney St Boston, Ma 02115
Grant 1DP1OD000839-01 from Office Of The Director, National Institutes Of Health IRG: ZGM1
Abstract: Recent studies have focused attention on the role of mitogenic niches in regulating stem cell self?renewal, and have emphasized the importance of proteoglycans in forming such microenvironments. However, more than 50 years after the genetic code was deciphered, we do not know whether sugar chains on proteoglycans encode biologically important information. The potential complexity of such a ?glyco code? is enormous, but little is known about the features of the proteoglycans involved in mitogenic regulation, or the signaling mechanisms required for stem cell renewal. To decipher whether there is a glyco code we will identify proteoglycans that specify stem cell renewal in the mammalian brain. We will rely on a genetic approach to proteoglycan biology and on newly developing innovations in mass spectrometry that allow large scale analysis of the sugar composition of proteoglycans. We will generate mutated growth factors capable of binding to cognate receptors, but unable to bind proteoglycans. We will ascertain whether individual proteoglycans modulate the signaling pathway and the biological response elicited by a growth factor, perhaps by influencing the location, presentation, or oligomerization of the factor. We will begin by focusing on Sonic Hedgehog (Shh), which is mitogenic for stem cells in the cerebellum, cortex, and in diverse cancers. We will identify proteoglycans required for Shh- mediated proliferation using a new assay for mitogenic niches, and we will determine how a glyco code might regulate stem cell propagation. As the work progresses we will extend our studies to define proteoglycan structures that modulate the response of stem cells to additional agents such as EGF or FGF family members. These studies will contribute to the identification of a glyco-code, and will determine mechanisms that maintain ?stemness?. Such studies can lead to enhanced therapies for disorders from Alzheimers disease to cancers to stroke.
Keywords: biological signal transduction, cell proliferation, chemical structure function, mitogen, proteoglycan, regeneration, stem cell, cell transformation, chemical binding, genetic regulation, granule cell, growth factor, neoplastic process, sonic hedgehog gene /protein, NIH Roadmap Initiative tag, mass spectrometry
Project start date: 2006-09-28
Project end date: 2011-07-31
1DP1OD000839-01 (2006): $854584
Trafficking Of Neurotrophic Receptors In ALS
Rosalind A Segal, Associate Professor
Dana-farber Cancer Institute 44 Binney St Boston, Ma 02115
Grant 5R21NS049381-02 from National Institute Of Neurological Disorders And Stroke IRG: ZNS1
Abstract: Recent data that mutations in genes encoding dynein components cause Amyotrophic Lateral Sclerosis indicate that dynein function and retrograde axonal transport are required for motor neuron survival. However, the critical molecules transported by dynein motors are not known. Neurotrophins, peptide growth factors released by targets of innervation, initiate a survival signal that must be propagated through the axon. Cell death in Amyotrophic Lateral Sclerosis (ALS), then, may result from impaired transport of a long-range neurotrophin survival signal. In the proposed studies, we will test the hypothesis that long distance signaling by neurotrophins requires intracellular transport processes that are aberrant in ALS. In support of this hypothesis, we have found that dynein function within axons is required for survival of neurons that depend on target-derived neurotrophic factors. In the proposed experiments we will investigate the nature of the intracellular trafficking responsible for retrograde transport of Trk receptors. We will determine whether mutations that cause ALS in humans impede neurotrophin retrograde signaling. These experiments will provide insight into the pathogenesis of ALS, and identify potential therapeutic targets. We have three specific aims Aim 1 To test the hypothesis that neurodegeneration in ALS results from the loss of long range neurotrophin signaling. To determine whether genetic changes that predispose to motor neuron degeneration impair retrograde neurotrophin signaling, we will use SOD-1 mice (transgenics expressing the SOD-1 G93A mutation). We will ask whether retrograde neurotrophin signaling is impaired in the neurons of these animals fated to develop ALS. Aim 2 To determine whether Alsin, the product of the ALS2 gene at 2q33-35, is required for vesicular trafficking of Trk receptors and for retrograde signaling by neurotrophins. Mutations in ALS2 have been implicated in a large number of familial motor neuron disorders. Alsin, the protein encoded by ALS2, is a guanine nucleotide exchange factor for the endosomal protein Rab5, and facilitates endocytic sorting in the nervous system. We will determine whether impaired Alsin function results in a loss of neurotrophin survival signals. Aim 3 To identify the nature of the dynein motors that transport long range survival signals, and whether these are assembled in response to neurotrophin stimulation. The composition of dynein motor complexes varies based on the cargo that is transported. We will take both a candidate approach and a proteomic approach to identify components of the motor that transports activated Trks, and whether these motors are regulated by neurotrophins. Taken together, these studies will determine how defects in axonal transport cause selective degeneration of motor neurons. The identification of survival signals that depend on transport, and the transport mechanisms, will lead to new therapeutic approaches to ALS.
Keywords: amyotrophic lateral sclerosis, biological signal transduction, dynein ATPase, neural degeneration, neuronal transport, neurotrophic factor, axon, degenerative motor system disease, gene mutation, growth factor receptor, guanine nucleotide exchange factor, nerve growth factor, neuropathology, protein transport, superoxide dismutase, clinical research, genetically modified animal, human tissue, immunocytochemistry, laboratory mouse, laboratory rat, polymerase chain reaction, postmortem, western blotting
Project start date: 2004-03-01
Project end date: 2006-02-28
5R21NS049381-02 (2005): $237263
1R21NS049381-01 (2004): $197719
Sponsored Links Excellgen http://Excellgen.com
CELL/CELL INTERACTIONS IN CEREBELLAR DEVELOPMENT
Rosalind A Segal, Associate Professor
Beth Israel Deaconess Medical Center
330 Brookline Avenue, Br 264
boston, Ma 02215
Grant 1R01NS037757-01 from National Institute Of Neurological Disorders And Stroke IRG: NEUB
Abstract: Purkinje cells are the sole output from the cerebellar cortex, and so diseases that alter Purkinje cell develop and function have devastating effects on balance and coordination. My colleagues and I have demonstrated that the neurotrophin, BDNF, is necessary for normal Purkinje cell development, particularly for dendritic arborization. In the proposed research we will identify the cells that synthesize BDNF to regulate Purkinje cell development and determine whether the p75 receptor plays a role in this regulation. We will investigate further the nature of the biological effects of BDNF on Purkinje cells, to determine whether BDNF regulates Purkinje cell synapses. Specific aim 1 is to test the hypothesis that BDNF synthesized and released by granule cell acts in an anterograde fashion to regulated Purkinje cell development; we will also examine the alternative possibilities that BDNF is instead involved in the interactions of climbing fiber or deep cerebellar nuclei neurons with Purkinje cells. We will use genetic or mechanical means to remove granule cells in vivo or remove afferent connections to the cerebellar cortex, and determine whether Purkinje still accumulate BDNF and undergo Trk phosphorylation. We will use organotypic and dissociated cell cultures to determine whether BDNF is required for granule cells to regulate Purkinje cell dendritic arborization. Specific aim 2 is to test the hypothesis that both TrkB and the p75 receptor mediate the effects of BDNF in developing Purkinje cells. While our previous work has demonstrated that activation of the TrkB receptor is a critical component in the Purkinje cell response to BDNF, others have shown that antibodies to p75 perturb Purkinje cell dendritic growth and survival, suggesting that both receptors may participate in the BDNF response. We will analyze Purkinje cell morphology, cerebellar foliation, Trk phosphorylation and BDNF uptake in p75/BDNF compound mutant mice. These experiments will indicate signal transduction pathways critical for regulating Purkinje cell development. Specific aim 3 is to test the hypothesis that BDNF is involve din the formation and maturation of granule cell-Purkinje cell synapses. We will use structural, biochemical and electrophysiologic approaches to compare parallel fiber Purkinje cell synapses in wild type and BDNF-/- mice, and to evaluate acute and chronic effects of BDNF on Purkinje cell synapses. These studies will identify extracellular factors that regulate Purkinje cell development, and could provide the basis for therapeutic applications of neurotrophic factors on drugs in treating cerebellar diseases
Keywords: cell cell interaction, cell growth regulation, cerebellar Purkinje cell, granule cell, neurotrophic factor biological signal transduction, growth factor receptor, phosphorylation, synapse immunocytochemistry, laboratory mouse, nervous system transplantation, tissue /cell culture
Project start date: 1998-09-30
Project end date: 1998-10-31
1R01NS037757-01 (1998): $240647
NEW APPROACHES TO LOCAL TRANSLATION: SPACESTAMP OF PROTEINS SYNTHESIZED IN AXONS
Rosalind A Segal, Professor Of Neurobiology
Dana-farber Cancer Institute, 44 Binney St, Boston, Ma 02115
Grant 1R01MH091662-01 from National Institute Of Mental Health
Abstract: For many years, conventional wisdom declared that no protein translation occurs in the axons of mammalian neurons. Instead all proteins needed for axonal functions were supposed to be synthesized in the cell bodies and shipped out to the axons. More recently, accumulating data has provided evidence that many mRNAs are found in axons in the mammalian nervous system. Evidence indicating that local translation in axons may be regulated by electrical activity, neurotrophic factors, and stress, have led to the hypothesis that axonal translation is particularly important for plasticity during learning, or in response to environmental stressors. In support of this idea, defects in local translation have been linked to Fragile X syndrome, which causes cognitive problems and autistic behaviors, and paraneoplastic disorders, which cause encephalitis in some patients with lung cancers. However, the mechanisms regulating local translation, and why defects in local translation lead to neuro-psychiatric dysfunction, are not understood. In part, this reflects the inadequacy of current approaches for analyzing local protein synthesis or identifying biological functions that rely on regulated local translation. To address this problem we initiated a collaboration with Michael Lin. Michael recently developed a technique called timeSTAMP, to identify proteins that are translated at a particular time period (4). We are working with Michael to modify this approach so it can be used for spaceSTAMP, to tag proteins translated in a particular location, and follow them over time and space. The goal of this proposal is develop the spaceSTAMP approach and use it to ask Is there regulated local translation in axons? Are such locally translated proteins functionally important? Are locally translated proteins restricted to the axonal compartment, or do they facilitate communication between axonal terminals and remote portions of the neuronal cell body? These studies will develop and test a spaceSTAMP technique that allows one to tag proteins synthesized in axons, and to follow these components in time and space. This approach can then be used by the scientific community to solve problems such as the functional importance of the fragile X gene product, and ways in which activity or neurotrophin regulated translation contribute to neuro-psychiatric disorders. These studies will develop a new technique that we call spaceSTAMP. This technique allows one to tag proteins made in one part of the cell and to follow these components as they move in time and space. This approach will enable the scientific community to understand diseases that affect local protein synthesis; these diseases include Fragile X syndrome, one of the most common inherited causes of developmental delay and of autism
Keywords: Actins; Address; Affect; Antibodies; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Axon; Axon Terminals; Binding Proteins; Biological; Biological Function; Biological Process; Cancer of Lung; Cell Body; Cell Function; Cell Process; Cell physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Child Development Disorders, Specific; Cleaved cell; Cognitive; Collaborations; Communication; Communities; Covalent Interaction; Data; Defect; Developmental Delay; Developmental Delay Disorders; Disease; Disorder; Distal; Dysfunction; Encephalitis; Escalante syndrome; Esteroproteases; FMRP; Figs; Figs - dietary; Fragile X; Fragile X Gene; Fragile X Syndrome; Functional disorder; Goals; Hereditary; Inflammation, Brain; Inherited; Kanner`s Syndrome; Lead; Learning; Left; Ligand Binding Protein; Limbic Encephalitis; Link; Location; Malignant Tumor of the Lung; Malignant neoplasm of lung; Martin-Bell Syndrome; Martin-Bell-Renpenning syndrome; Mental Retardation; Mental disorders; Mental health disorders; Messenger RNA; Method LOINC Axis 6; Methodology; Methods; Methods and Techniques; Methods, Other; Mitochondria; NRVS-SYS; Nerve Cells; Nerve Endings, Presynaptic; Nerve Unit; Nervous System; Nervous system structure; Neural Cell; Neurocyte; Neurologic Body System; Neurologic Organ System; Neurons; Paraneoplastic Limbic Encephalitis; Paraneoplastic Syndromes; Patients; Pb element; Peptidases; Peptide Biosynthesis, Ribosomal; Peptide Hydrolases; Physiopathology; Presynaptic Terminals; Problem Solving; Proteases; Protein Biosynthesis; Protein Biosynthesis, Ribosomal; Protein Synthesis, Ribosomal; Proteinases; Proteins; Proteolytic Enzymes; Psychiatric Disease; Psychiatric Disorder; Pulmonary Cancer; Pulmonary malignant Neoplasm; RNA, Messenger; RNA-Binding Proteins; Renpenning syndrome 2; Role; Shipping; Ships; Stress; Subcellular Process; Synaptic Boutons; Synaptic Terminals; Techniques; Testing; Time; Translating; Translatings; Translations; Unspecified Mental Disorder; Work; X-linked mental deficiency-megalotestes syndrome; X-linked mental retardation with fragile X syndrome; X-linked mental retardation-fragile site 1 syndrome; autism-fragile X (AFRAX) syndrome; autism-fragile X syndrome; autistic behavior; autistic behaviour; cell body (neuron); cleaved; disease/disorder; environmental stressor; fra(X) syndrome; fra(X)(28) syndrome; fra(X)(q27) syndrome; fra(X)(q27-28) syndrome; fragile X-mental retardation syndrome; fragile Xq syndrome; fragile site mental retardation 1; fragile x [{C0016667}]; fragile x syndromes; gene product; heavy metal Pb; heavy metal lead; language translation; lung cancer; mRNA; macro-orchidism-marker X (MOMX) syndrome; macro-orchidism-marker X syndrome; mar(X) syndrome; marker X syndrome; mental illness; mental retardation-macroorchidism syndrome; mitochondrial; neural cell body; neuronal; neuronal cell body; neuropsychiatric; neuropsychiatry; neurotrophic factor; neurotrophin; neutrophin; new approaches; novel approaches; novel strategies; novel strategy; pathophysiology; protein synthesis; psychological disorder; public health relevance; response; social role; soma; transcription factor
Relevance: Narrative These studies will develop a new technique that we call spaceSTAMP. This technique allows one to tag proteins made in one part of the cell and to follow these components as they move in time and space. This approach will enable the scientific community to understand diseases that affect local protein synthesis; these diseases include Fragile X syndrome, one of the most common inherited causes of developmental delay and of autism
Project start date: 2010-06-08
Project end date: 2014-03-31
Budget start date: 8-JUN-2010
Budget end date: 31-MAR-2011
PFA/PA: RFA-GM-10-009
1R01MH091662-01 (2010): $161094
Cell-cell Interactions2 In Cerebellar Development
Rosalind A Segal, Associate Professor
Dana-farber Cancer Institute 44 Binney St Boston, Ma 02115
Grant 2R01NS037757-06A1 from National Institute Of Neurological Disorders And Stroke IRG: MDCN
Abstract: During development of the nervous system, precursor cells divide in specialized proliferative zones, then migrate away from these zones and differentiate. The mechanisms that allow coordinated cell cycle exit and directed migration can readily be examined in the developing cerebellum. In studies supported by this grant, my colleagues and I identified two extracellular factors that regulate migration of cerebellar precursors stromal cell derived factor (SDF-1 alpha) and brain derived neurotrophic factor (BDNF). We demonstrated that mice with targeted gene deletions of either SDF-1alpha or of BDNF exhibit both aberrant migration and proliferation of neuronal precursors in the cerebellum. In the proposed studies we will define the mechanisms whereby these factors stimulate migration, and how they coordinately influence proliferation. 1. The first specific aim is to determine the mechanism by which BDNF promotes granule cell migration. We will use genetic and pharmacologic tools to identify the signal transduction pathways required for directed migration, focusing on the possibility that TrkB activity stimulates PI3 kinase to promote cell migration. 2. The second specific aim is to test the hypothesis that a gradient of BDNF causes redistribution of TrkB receptors to amplify the gradient and provide a direction for chemotaxis. Preliminary data indicate that BDNF induces an asymmetric distribution of the BDNF receptor, TrkB, with accumulation of receptors at the leading edge. We will test the hypothesis that redistribution of TrkB receptors allows amplification of the gradient, determine whether TrkB redistribution reflects movement of surface receptors or the addition of new receptors to the surface, and determine whether receptor redistribution is needed for chemotaxis. 3. The third specific aim is to test the hypothesis that SDF-1alpha functions as a spatially restricted competence factor that limits SHH-induced proliferation to the EGL. We will investigate the possibility that SHH and SDF function as competence and progression factors for precursor proliferation, and identify transcriptional targets that depend on the synergy of these two factors Taken together, these studies will identify mechanisms that regulate the directed migration of granule cells, and define the relationship between migration and proliferation. Since unregulated migration and proliferation are the hallmarks of malignancy, these studies will provide a basis for understanding and treating brain tumors.
Keywords: brain derived neurotrophic factor, cell cell interaction, cell growth regulation, cell migration, cell proliferation, cerebellar Purkinje cell, granule cell, biological signal transduction, enzyme induction /repression, growth factor receptor, phosphatidylinositol 3 kinase, phosphorylation, protein tyrosine kinase, synapse, confocal scanning microscopy, green fluorescent protein, immunocytochemistry, laboratory mouse, laboratory rat, nervous system transplantation, tissue /cell culture
Project start date: 1998-09-30
Project end date: 2007-03-31
2R01NS037757-06A1 (2003): $324900
Rosalind A Segal
Dana-farber Cancer Institute
Project start date: 2011-02-16
Project end date: 2016-01-31
RETROGRADE SIGNAL TRANSDUCTION BY NEUROTROPHINS
Rosalind A Segal, Associate Professor
Beth Israel Deaconess Medical Center 330 Brookline Avenue, Br 264 Boston, Ma 02215
Grant 1R01NS035148-01 from National Institute Of Neurological Disorders And Stroke IRG: NEUC
Project start date: 1996-05-01
Project end date: 1999-04-30
1R01NS035148-01 (1996): $324940