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Plenary Lectures
Int. J. Devl Neuroscience 19 (2001) 685– 686 www.elsevier.com/locate/ijdevneu
Abstracts Plenary Lectures PL2 PL1 Gene Regulation and Neural Development: ATF’s and Beyond L.A. GREENE 1, B. TO8 RO8 CSIK 1, C.L. MENDELSOHN 1, D. STAINDLER 2, V. KUKEKOV 2, T.N. IGNATOVA 2 and J.M. ANGELASTRO 1, 1Department of Pathology, Columbia Uni6ersity College of Physicians and Surgeons, New York, NY and 2Department of Neurobiology, Uni6ersity of Florida, Gaines6ille, FL A variety of studies have established that the mechanism of trophic-factor stimulated neuronal differentiation includes and requires specific changes in gene expression. To better understand the nature of these changes, we have used serial analysis of gene expression (SAGE) technology to obtain a comprehensive view of gene expression associated with responses to Nerve Growth Factor (NGF). Experiments were carried out with the NGF-responsive PC12 line of rat pheochromocytoma cells. Over 22,000 unique transcripts have been detected and quantified. Of these, approximately 4% undergo changes in expression by six-fold or more in response to long-term (9 days) NGF exposure. Additional genes were found that undergo significant regulation of expression at 1 h of NGF treatment. Categorization of the regulated transcripts that encode proteins of known function provides an over-view of how NGF promotes neuronal differentiation. In addition, functional studies have commenced on regulated genes encoding proteins whose roles in neuronal differentiation are less clear. One example of these includes the transcription factor ATF5, which undergoes 26-fold down-regulation in response to long-term NGF treatment. Functional and developmental studies of this factor reveal that it may play a crucial role in the transition between dividing precursor cells and post-mitotic neurons. A second example is the transcription factor MAFK which responds to NGF as an immediate early gene and which functional studies indicate plays a significant role in neuritogenesis.
PII: S 0 7 3 6 - 5 7 4 8 ( 0 1 ) 0 0 0 5 7 - 0
Linking Brain Development and Behaviour L.J. ROGERS, School of Biological Sciences, Uni6ersity of New England, Armidale, NSW 2351, Australia Associations between neural development and changes in behaviour can be more easily made in precocial than in altricial species because the former undergo a series of discrete phases of development that can be related and manipulated. The developing chick has proved to be a useful model for this reason. The added attribute of having differential specialization of the forebrain hemispheres has made the chick a model system for studies aimed at elucidating the interactions between genetic, hormonal and experiential influences on development. Experience-dependent development of the visual pathways of the chick begins prior to hatching. During the final stages of incubation, and under the influence of specific gene expression, the embryo is positioned within the egg so that it occludes its left eye but its right eye is exposed to light stimulation (unpatterned light passing through the shell). This lateralized stimulation leads to asymmetrical expression of c-fos in the Wulst region of the forebrain and to asymmetrical development of the thalamofugal visual projections. Hence light experience leads to a lateralized visual responses in chicks after hatching, shown as left– right eye differences in responding to food, conspecifics and predators. Incubation in the dark prevents the development of some of these asymmetries and not others, as will be discussed. Steroid hormones modulate the sensitivity of the developing neurons to light (e.g. raised levels of corticosterone in the embryo prevent the development of asymmetry). These hormonal effects and also sequential changes in hemispheric dominance during development will be discussed.
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686
Abstracts/Int. J. De6l Neuroscience 19 (2001) 685–686
PL3
PL4
The Regulation of Neuronal Survival and Growth by Trk Receptors D. KAPLAN, Brain Tumor Research Centre, Montreal Neurological Institute, McGill Uni6ersity, Montreal, PQ, Canada H3A 2B4
Neuronal Plasticity at Growth Cones and Synapses MU-MING POO, Department of Molecular and Cell Biology, Di6ision of Neurobiology, Uni6ersity of California, Berkeley, CA 94720, USA
Neurotrophins regulate the surviaval, axonal growth, and regeneration of neurons by interacting with their receptors, the Trk tyrosine kinases and the p75NTR. These two receptors can either collaborate or inhibit each others actions. The development and survival of neurons is thus based upon the functional interplay of the signals generated by Trk and p75NTR. Recent advances by our group and others have identified the signaling pathways used by these receptors in peripheral neurons, including Akt, MAPK, and p73-induced signaling via Trk, and JNK and p53 signaling via p75NTR. Survival signals mediated by Trk primarily use the PI-3 kinase/Akt signalling pathway, with the MEK/MAPK pathway playing a secondary role. These survival pathways function to suppress apoptotic signals induced by the p75NTR, including the JNK/p53/BAX pathway. However, to assure that too much neurotrophin signaling does not occur during development, Trk modulates its own pro-survival signals by binding to and activating the SHP-1 phosphotyrosine phosphatase Axonal growth regulated by the neurotrophins occurs primarily through MEK/MAPK and PI-3 kinase, while growth repellent or inhibitory signals mediated by semaphorins function by suppressing Trk-induced MEK/MAPK and PI-3 kinase activity at the growth cone. Mice in which MEK activity is suppressed only in neurons show markedly decreased sympathetic and sensory target innervation, with no alterations in neuronal survival. Other signals mediated by Rac1 regulate both target innervation and the regeneration of neurons.
The formation of intricate neural networks in the nervous system depends on the pathfinding of axonal growth cones to reach their correct target cells as well as activity-driven refinement of neuronal connections after initial synaptic contacts have been made. In this lecture, I will summarize our recent findings on the cellular mechanisms underlying the guidance of growth cones and refinement of developing synapses. On the mechanisms of growth and cone guidance, I will discuss our studies on the cytoplasmic events associated with the growth cone turning responses induced by gradients of extracellular guidance cues. I will address the critical role of cyclic nucleotides and calcium ions in determining the attractive and repulsive turning responses of the growth cone. I will also discuss how the growth cone may amplify the gradient signal provided by the guidance cue, and how the growth cone may readjust its sensitivity toward the guidance cue as it moves up the gradient. On the acti6ity-induced modifications of neural circuits, I will discuss our findings using developing Xenopus retinotectal system —how the temporal pattern of electrical activity may determine the nature of synaptic modification, how multiple converging synapses on the postsynaptic cell cooperate with or compete against one another in achieving the refinement of developing connections, and how visual experience may shape the development of receptive field properties of tectal neurons. Here, the pattern of postsynaptic elevation of calcium ions plays a critical role in setting the polarity (potentiation or depression) of synaptic modification. These studies of growth cone guidance and synaptic modifications illustrate a common theme in the cellular mechanism underlying neuronal plasticity: environmental (epigenetic) factors set a cytoplasmic pattern of second messengers, which in turn shift the balance of antagonistic cellular signaling events, leading to alternative cellular responses.
Abstracts Plenary Lectures PL2 PL1 Gene Regulation and Neural Development: ATF’s and Beyond L.A. GREENE 1, B. TO8 RO8 CSIK 1, C.L. MENDELSOHN 1, D. STAINDLER 2, V. KUKEKOV 2, T.N. IGNATOVA 2 and J.M. ANGELASTRO 1, 1Department of Pathology, Columbia Uni6ersity College of Physicians and Surgeons, New York, NY and 2Department of Neurobiology, Uni6ersity of Florida, Gaines6ille, FL A variety of studies have established that the mechanism of trophic-factor stimulated neuronal differentiation includes and requires specific changes in gene expression. To better understand the nature of these changes, we have used serial analysis of gene expression (SAGE) technology to obtain a comprehensive view of gene expression associated with responses to Nerve Growth Factor (NGF). Experiments were carried out with the NGF-responsive PC12 line of rat pheochromocytoma cells. Over 22,000 unique transcripts have been detected and quantified. Of these, approximately 4% undergo changes in expression by six-fold or more in response to long-term (9 days) NGF exposure. Additional genes were found that undergo significant regulation of expression at 1 h of NGF treatment. Categorization of the regulated transcripts that encode proteins of known function provides an over-view of how NGF promotes neuronal differentiation. In addition, functional studies have commenced on regulated genes encoding proteins whose roles in neuronal differentiation are less clear. One example of these includes the transcription factor ATF5, which undergoes 26-fold down-regulation in response to long-term NGF treatment. Functional and developmental studies of this factor reveal that it may play a crucial role in the transition between dividing precursor cells and post-mitotic neurons. A second example is the transcription factor MAFK which responds to NGF as an immediate early gene and which functional studies indicate plays a significant role in neuritogenesis.
PII: S 0 7 3 6 - 5 7 4 8 ( 0 1 ) 0 0 0 5 7 - 0
Linking Brain Development and Behaviour L.J. ROGERS, School of Biological Sciences, Uni6ersity of New England, Armidale, NSW 2351, Australia Associations between neural development and changes in behaviour can be more easily made in precocial than in altricial species because the former undergo a series of discrete phases of development that can be related and manipulated. The developing chick has proved to be a useful model for this reason. The added attribute of having differential specialization of the forebrain hemispheres has made the chick a model system for studies aimed at elucidating the interactions between genetic, hormonal and experiential influences on development. Experience-dependent development of the visual pathways of the chick begins prior to hatching. During the final stages of incubation, and under the influence of specific gene expression, the embryo is positioned within the egg so that it occludes its left eye but its right eye is exposed to light stimulation (unpatterned light passing through the shell). This lateralized stimulation leads to asymmetrical expression of c-fos in the Wulst region of the forebrain and to asymmetrical development of the thalamofugal visual projections. Hence light experience leads to a lateralized visual responses in chicks after hatching, shown as left– right eye differences in responding to food, conspecifics and predators. Incubation in the dark prevents the development of some of these asymmetries and not others, as will be discussed. Steroid hormones modulate the sensitivity of the developing neurons to light (e.g. raised levels of corticosterone in the embryo prevent the development of asymmetry). These hormonal effects and also sequential changes in hemispheric dominance during development will be discussed.
.
686
Abstracts/Int. J. De6l Neuroscience 19 (2001) 685–686
PL3
PL4
The Regulation of Neuronal Survival and Growth by Trk Receptors D. KAPLAN, Brain Tumor Research Centre, Montreal Neurological Institute, McGill Uni6ersity, Montreal, PQ, Canada H3A 2B4
Neuronal Plasticity at Growth Cones and Synapses MU-MING POO, Department of Molecular and Cell Biology, Di6ision of Neurobiology, Uni6ersity of California, Berkeley, CA 94720, USA
Neurotrophins regulate the surviaval, axonal growth, and regeneration of neurons by interacting with their receptors, the Trk tyrosine kinases and the p75NTR. These two receptors can either collaborate or inhibit each others actions. The development and survival of neurons is thus based upon the functional interplay of the signals generated by Trk and p75NTR. Recent advances by our group and others have identified the signaling pathways used by these receptors in peripheral neurons, including Akt, MAPK, and p73-induced signaling via Trk, and JNK and p53 signaling via p75NTR. Survival signals mediated by Trk primarily use the PI-3 kinase/Akt signalling pathway, with the MEK/MAPK pathway playing a secondary role. These survival pathways function to suppress apoptotic signals induced by the p75NTR, including the JNK/p53/BAX pathway. However, to assure that too much neurotrophin signaling does not occur during development, Trk modulates its own pro-survival signals by binding to and activating the SHP-1 phosphotyrosine phosphatase Axonal growth regulated by the neurotrophins occurs primarily through MEK/MAPK and PI-3 kinase, while growth repellent or inhibitory signals mediated by semaphorins function by suppressing Trk-induced MEK/MAPK and PI-3 kinase activity at the growth cone. Mice in which MEK activity is suppressed only in neurons show markedly decreased sympathetic and sensory target innervation, with no alterations in neuronal survival. Other signals mediated by Rac1 regulate both target innervation and the regeneration of neurons.
The formation of intricate neural networks in the nervous system depends on the pathfinding of axonal growth cones to reach their correct target cells as well as activity-driven refinement of neuronal connections after initial synaptic contacts have been made. In this lecture, I will summarize our recent findings on the cellular mechanisms underlying the guidance of growth cones and refinement of developing synapses. On the mechanisms of growth and cone guidance, I will discuss our studies on the cytoplasmic events associated with the growth cone turning responses induced by gradients of extracellular guidance cues. I will address the critical role of cyclic nucleotides and calcium ions in determining the attractive and repulsive turning responses of the growth cone. I will also discuss how the growth cone may amplify the gradient signal provided by the guidance cue, and how the growth cone may readjust its sensitivity toward the guidance cue as it moves up the gradient. On the acti6ity-induced modifications of neural circuits, I will discuss our findings using developing Xenopus retinotectal system —how the temporal pattern of electrical activity may determine the nature of synaptic modification, how multiple converging synapses on the postsynaptic cell cooperate with or compete against one another in achieving the refinement of developing connections, and how visual experience may shape the development of receptive field properties of tectal neurons. Here, the pattern of postsynaptic elevation of calcium ions plays a critical role in setting the polarity (potentiation or depression) of synaptic modification. These studies of growth cone guidance and synaptic modifications illustrate a common theme in the cellular mechanism underlying neuronal plasticity: environmental (epigenetic) factors set a cytoplasmic pattern of second messengers, which in turn shift the balance of antagonistic cellular signaling events, leading to alternative cellular responses.