Nutritional Modulation Of Lifespan In Drosophila
Kai G Zinn, Professor
California Institute Of Technology
office Of Sponsored Research, Mail Code 201-15
pasadena, Ca 91125
Grant 5R01AG024366-05 from National Institute On Aging IRG: ZAG1
Abstract: Caloric restriction (CR), a decrease in nutritional level without causing malnutrition, is well known to increase lifespan across species, from yeast to rodents. Ad libitum feeding can therefore be viewed as having a toxic effect on lifespan. Indeed, overnutrition in humans is one of the leading risk factors for age-related diseases and mortality. We propose to characterize the effects of overnutrition in Drosophila, and seek ways to mitigate them by finding mutants that show either enhanced sensitivity or resistance to overnutrition. The identification of molecular pathways involved should provide tools in the understanding of this phenomenon, by leading us to the downstream genes that manifest the lifespan changes. Examination of the pathological and physiological changes resulting from overnutrition in normal and mutant flies will cast light on their involvement in aging and age-related diseases. Most investigations have been directed at the effects of undernutrition as a beneficial factor in extending lifespan. This proposal represents an alternate approach, focusing on overnutrition to exaggerate deleterious effects, thus providing a sensitized system in which to discover methods of ameliorating them
Keywords: bioenergetics, biological model, caloric dietary content, dietary restriction, longevity, nutrient intake activity, nutrition of aging, overeating autophagy, cell component structure /function, developmental genetics, gene environment interaction, gene expression, genetic regulation, geriatrics, hormone regulation /control mechanism, insulin, mitochondria, protein structure function, transcription factor Drosophilidae, nutrition related tag
Project start date: 2004-09-15
Project end date: 2009-06-30
5R01AG024366-05 (2008): $371485
Sponsored Links Excellgen http://Excellgen.com
Nutritional Modulation Of Lifespan In Drosophila
Kai G Zinn, Professor
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01AG024366-04 from National Institute On Aging IRG: ZAG1
Abstract: Caloric restriction (CR), a decrease in nutritional level without causing malnutrition, is well known to increase lifespan across species, from yeast to rodents. Ad libitum feeding can therefore be viewed as having a toxic effect on lifespan. Indeed, overnutrition in humans is one of the leading risk factors for age-related diseases and mortality. We propose to characterize the effects of overnutrition in Drosophila, and seek ways to mitigate them by finding mutants that show either enhanced sensitivity or resistance to overnutrition. The identification of molecular pathways involved should provide tools in the understanding of this phenomenon, by leading us to the downstream genes that manifest the lifespan changes. Examination of the pathological and physiological changes resulting from overnutrition in normal and mutant flies will cast light on their involvement in aging and age-related diseases. Most investigations have been directed at the effects of undernutrition as a beneficial factor in extending lifespan. This proposal represents an alternate approach, focusing on overnutrition to exaggerate deleterious effects, thus providing a sensitized system in which to discover methods of ameliorating them.
Keywords: bioenergetics, biological model, caloric dietary content, dietary restriction, longevity, nutrient intake activity, nutrition of aging, overeating, autophagy, cell component structure /function, developmental genetics, gene environment interaction, gene expression, genetic regulation, geriatrics, hormone regulation /control mechanism, insulin, mitochondria, protein structure function, transcription factor, Drosophilidae, nutrition related tag
Project start date: 2004-09-15
Project end date: 2009-06-30
5R01AG024366-04 (2007): $379067
Grants awarded to Kai G Zinn
MOLECULAR GENETICS OF DROSOPHILA CNS DEVELOPMENT
Kai G Zinn, Professor
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01NS028182-14 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: We seek to understand the molecular and cellular mechanisms that determine synaptic connectivity in developing nervous systems. Our work primarily focuses on motor axon guidance and synaptogenesis in the neuromuscular system of the Drosophila embryo. This system is attractive because it contains only 34 motoneurons and 30 muscle fibers, and the pattern of neuromuscular connections is genetically determined and essentially invariant between embryos. Most neural structures in mammals are much more complicated, and mammalian neurons are usually not individually specified. Nevertheless, many of the molecules and mechanisms involved in process outgrowth, axon guidance, and synaptogenesis are conserved between flies and humans. Thus, the results of our studies are likely to be relevant to an understanding of human neural development. We have concentrated on a group of cell surface/signal transduction molecules, the axonal receptor-linked protein-tyrosine phosphatases (RPTPs), and have shown that they control specific motor axon guidance decisions. Some of these RPTPs have mammalian counterparts with very similar structures (e.g., fly DLAR and human LAR), and RPTPs in vertebrates are also expressed in neuronal processes. We now wish to advance our understanding of the mechanisms involved in axon guidance by characterizing genetic and biochemical interactions among the RPTPs. We will focus on two RPTPs (DPTP99A and DLAR) that oppose each other s signaling pathways in which these and other RPTPs function. This will be done by examining interactions with the transmembrane proteins gp150 and Appl, which bind to and are substrates for fly RPTPs, and by conducting a biochemical a biochemical screen for new substrates using the recently developed substrate trap method. We will also attempt to identify cell-surface ligands for RPTPs using expression cloning techniques. Finally, we will perform a genetic screen for new cell recognition/signaling molecules involved in axon guidance and synaptogenesis. This modular misexpression P element screen is designed to identify genes for which over-expression in all muscles or all neurons produces axon guidance phenotypes. Some of the proteins encoded by which genes might function in RPTP signaling most are likely to be involved in different pathways and processes. We are especially interested in cell-surface proteins that control innervation of individual muscle fibers, a process that is still poorly understood.
Keywords: Drosophilidae, developmental neurobiology, neurogenetics, neuronal guidance, protein tyrosine phosphatase, synaptogenesis, biological signal transduction, enzyme substrate, gene deletion mutation, genetic promoter element, protein protein interaction, receptor expression, transposon /insertion element, complementary DNA, expression cloning, genetic library, immunoprecipitation, laboratory mouse, larva, tissue /cell culture, transgenic animal
Project start date: 1990-01-01
Project end date: 2004-01-31
5R01NS028182-14 (2003): $275067
5R01NS028182-13 (2002): $269293
5R01NS028182-12 (2001): $259417
5R01NS028182-11 (2000): $254096
Molecular Genetics Of CNS Development
Kai G Zinn, Professor
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01NS028182-18 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: This proposal focuses on a set of Drosophila neuronal cell surface signal transduction proteins, the receptor tyrosine phosphatases (RPTPs), which regulate axon guidance and synaptogenesis in embryos, larvae, and pupae. RPTPs are highly conserved between flies and humans, and mammalian RPTPs may also regulate axon guidance and synaptic function. The phenotypes of RPTPs mutations in Drosophila have been examined in detail. However, to understand how RPTPs function in axon guidance, it will be necessary to define their signaling pathways. It is especially important to characterize the ligands and/or co-receptors to which they bind and the substrates on which they act. Two specific aims of this proposal deal with the analysis of putative RPTP ligands or co-receptors that our group has recently identified, and the third concerns the characterization of candidate RPTP substrates. SAI We found that the secreted protein Folded Gastrulation (Fog) and the DPTP52F RPTP bind to each other. We now wish to determine if Fog is a ligand for DPTP52F in vivo. We will map the regions of DPTP52F involved in Fog interactions, measure binding affinities, and determine whether Fog affects phosphatase activity. Genetic interaction experiments will be performed to determine if Fog is required for DPTP52F signaling in vivo. SA2 We will study interactions of the DLAR RPTP with the heparan sulfate proteoglycan Syndecan. We identified Syndecan in a novel deficiency screen for genes encoding DLAR binding proteins. Lar and Syndecan (Sdc) mutations display strong genetic interactions, consistent with the hypothesis that Syndecan is required for DLAR function in vivo. We will perform biochemical experiments to measure the affinity of DLAR for Syndecan, map the regions of DLAR involved in Syndecan binding, and determine whether Syndecan affects enzymatic activity. Further genetic interaction experiments will be conducted in order to determine whether Syndecan is a ligand or a co receptor for DLAR. SA3 We identified four candidate RPTP substrates in a modified 2-hybrid yeast screen for clones that interact with substrate-trap mutants of the RPTPs in a phosphorylation dependent manner. We will perform biochemical experiments in transfected cells and transgenic flies to determine whether these are genuine RPTP substrates, and conduct genetic studies to analyze whether they are required for RPTP signaling in vivo.
Keywords: biological signal transduction, central nervous system, developmental neurobiology, enzyme activity, molecular genetics, neuronal guidance, protein tyrosine phosphatase, synaptogenesis, biochemistry, gene interaction, heparan sulfate, protein protein interaction, proteoglycan, syndecan, Drosophilidae, genetically modified animal, yeast two hybrid system
Project start date: 1990-01-01
Project end date: 2009-01-31
5R01NS028182-18 (2007): $355211
5R01NS028182-17 (2006): $365821
5R01NS028182-16 (2005): $374625
2R01NS028182-15 (2004): $374625
Signaling Mechanisms In Drosophila Neural Development
Kai G Zinn, Professor
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01NS043416-04 from National Institute Of Neurological Disorders And Stroke IRG: SYN
Abstract: This proposal concerns spastin and blue cheese beached (bchs), two genes identified in screens we conducted for genes involved in motor axon guidance and synaptogenesis in Drosophila larvae. We selected these genes for further study because they encode members of highly conserved but poorly understood protein families that have not been previously implicated in neural development. The two genes are not related to each other, but both encode proteins likely to be involved in protein trafficking within neurons and can be studied using similar methods. Both genes have orthologs or relatives affected in human genetic diseases. (1) The first gene, spastin, is the ortholog of a human gene affected in autosomal dominant spastic paraplegia (ADSP). spastin encodes an AAA ATPase. These ATPases are involved in catalyzing assembly and disassembly of protein complexes involved in vesicle trafficking, protein degradation, microtubule dynamics, and other processes. Analysis of an AAA ATPase sequence does not allow definition of the cellular process(es) in which it participates, however, so the targets of Spastin function are still unknown. Neuronal overexpression of spastin causes convergence of central nervous system (CNS) axons onto the midline, spastin loss-of-function (LOF) null mutant larvae display altered synaptic morphologies at their neuromuscular junctions (NMJs). They also have reduced evoked junctional potential (EJP) amplitudes, indicating that their NMJ synapses are abnormal. Spastin-null animals that survive to adulthood are unable to fly, walk poorly, and have a shortened lifespan. To further analyze Spastin function, we will complete the morphological and electrophysiological analysis of larval NMJs. We will also perform electrophysiological tests to examine why the mutant adults cannot fly and examine the adult brain for structural defects and neurodegeneration. We will examine the mechanisms involved in human ADSP by introducing mutations that cause spasticity in humans into the fly gene and determining if these act as dominant negatives in Drosophila. To define other components of the pathways(s) in which Spastin acts, we will perform an enhancer/suppressor genetic screen using a spastin gain-of-function (GOF) eye phenotype. Candidate genes emerging from the eye screen will be tested for modification of the spastin GOF axonal phenotype and for interaction with spastin LOF mutations. (2) The second gene, bchs, encodes a protein closely related to the founding member of the BEACH domain protein family the human protein whose loss causes Chediak-Higashi syndrome (CHS), a lethal genetic disease characterized by immunological and neurological defects. Cells from CHS patients contain abnormal giant lysosomes, bchs overexpression in neurons produces a unique phenotype in which bulges form at the junctions between motor axon trunks and side branches. bchs LOF mutations cause adult neurodegeneration phenotypes in the brain and eye, and bchs flies have short lifespans. In bchs larvae, some motor axon pathways are abnormally thickened, suggesting that individual axons are swollen or that additional axons have joined the pathways. Bchs contains a FYVE domain, which binds to phosphatidylinositol-3-phosphate (Ptdlns3P). It is a vesicular protein that occasionally colocalizes with a fluorescent marker (GFP-2XFYVE) for Ptdlns3P-containing endosomes; however, most Bchs vesicles are distinct from GFP-2XFYVE vesicles, suggesting that they represent different compartments. To study Bchs, we will analyze its subcellular localization and determine the vesicular compartment(s) in which it functions. We will examine bchs LOF and gain-of-function (GOF) phenotypes in the larval neuromuscular system using antibody staining, electron microscopy, and electrophysiology. We will also search for enhancers and suppressors of a bchs GOF eye phenotype. Candidate genes from the eye screen will be tested for modification of the bchs GOF neuromuscular phenotype and for interaction with bchs LOF mutations.
Keywords: biological signal transduction, developmental neurobiology, synaptogenesis, adenosinetriphosphatase, axon, gene expression, neural degeneration, neuromuscular junction, vesicle /vacuole, Drosophilidae, electron microscopy, electrophysiology, genetic screening, immunocytochemistry
Project start date: 2004-07-15
Project end date: 2008-03-31
5R01NS043416-04 (2007): $284171
Sponsored Links Excellgen http://Excellgen.com
5R01NS043416-03 (2006): $292658
5R01NS043416-02 (2005): $299700
1R01NS043416-01A2 (2004): $299700
PREDOCTORAL TRAINING IN BIOLOGY AND BIOPHYSICS
Kai G Zinn, Professor
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5T32GM007737-22 from National Institute Of General Medical Sciences IRG: BRT
Abstract: This program will provide predoctoral training of students preparing for research careers in Molecular, Cellular, and Systems Neuroscience. It involves 26 faculty members from the Biology, Physics, Chemistry, and Engineering Divisions. It is a continuation of a program previously supported by NIH. Some research areas of special emphasis are 1) neural development (control of cell fate, axon guidance and synaptogenesis in a variety of systems); 2) signal transduction mechanisms in neurons (sensory processing in the visual and olfactory systems of vertebrates and invertebrates, and synaptic transmission and plasticity in hippocampal neurons); 3) behavior (simple and complex behaviors in vertebrates, arthropods, and nematodes); 4) computational neuroscience (studies of single neurons, system of neurons, and whole organisms). The major components of our training activities are 1) each student s individual research program under one or more faculty sponsors; 2) an organized curriculum of graduate courses; 3) preparation for qualifying examinations; 4) teaching activities; 5) an extensive and wide-ranging seminar program. Support is requested for 16 predoctoral trainees, who will be admitted to graduate study for a Ph.D. in Biology or in Computation and Neural Systems. Criteria for admission into the program include a strong motivation for a career in research and high quantitative ability. Our expectation that trainees will continue into productive research careers is supported by the records of previous trainees. Caltech has a strong commitment (at both the institutional and the Divisional levels) to increasing the representation of minorities in science. In the Biology program, we have made special efforts to attract exceptionally talented students from under-represented minority groups, and we have been quite successful in this effort in recent years. A number of these students are primarily interested in neuroscience research. The training faculty are located within several building clustered near each other on the Caltech campus. Multi-user facilities include DNA sequencing, oligonucleotide synthesis, peptide synthesis, protein expression and purification, monoclonal antibody production, a transgenic and knockout mouse facility, and the Biological Imaging facility.
Project start date: 1979-07-01
Project end date: 2004-06-30
5T32GM007737-22 (2000): $237881
MOLECULAR ANALYSIS OF OLFACTORY SIGNAL TRANSDUCTION
Kai G Zinn, Professor
Institution:
Grant 5P50MH049176-050002 from National Institute Of Mental Health
Abstract: The primary goal of this project is to identify and characterize olfactory receptors for odorants. We plan to do this by developing assays for odorant receptor function in Xenopus oocytes. A pool of clones encoding a recently identified olfactory-specific 7-helix receptor family will be constructed and expressed in oocytes. The response to certain odorants thought to act by increasing inositol trisphosphate levels can then be directly assayed by electrophysiological measurements of C1- current. Most odorants are thought to increase cAMP levels, however, and no sensitive physiological assay for cAMP elevation in oocytes is currently available. We are thus attempting to develop such assays. The first assay method involves the construction of a Galpha protein that will interact with receptors that are normally coupled to adenylyl cyclase, but will instead cause activation of phospholipase C (leading to C1- channel opening). If this can be done, it will be of interest in its own right for G protein biology. The second and third methods will use expression of cAMP-regulated channels in oocytes to generate a current response to cAMP elevation. After a suitable assay is developed, we will use it to attempt to identify clones encoding receptors interacting with particular odorants. We will then express these receptors in cell lines to examine the mechanisms involved in olfactory signal transduction. We will also make receptor- specific antibodies to study in vivo receptor expression.
Keywords: G protein, chemoreceptor, olfaction, olfactory stimulus, receptor coupling, adenylate cyclase, antireceptor antibody, beta adrenergic receptor, chimeric protein, chloride channel, cyclic AMP, electrophysiology, inositol phosphate, phospholipase C, protein structure function, receptor expression, Xenopus oocyte, antisense nucleic acid, genetic library, immunoprecipitation, molecular cloning, polymerase chain reaction, tissue /cell culture, transfection
MOLECULAR GENETICS OF CNS DEVELOPMENT
Kai G Zinn, Professor
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01NS028182-09 from National Institute Of Neurological Disorders And Stroke IRG: NEUC
Abstract: The mechanisms involved in cell fate decisions and axon guidance during the development of the of the nervous system are still poorly understood. The study of these mechanisms in animal systems may provide information relevant to the understanding of fetal and postnatal development of the human nervous system. The segmental ganglia of the embryonic insect central nervous system (CNS) provide a useful system in which to study these processes, because they contain a relatively small number of neurons that make genetically defined pathway choices. The basic architecture of these ganglia is conserved between species with large neurons suitable for cell biology studies, such as the grasshopper Schistocerca, and species with well-developed genetics, such as the fruit fly Drosophila melanogaster. The growth cones of insect CNS neurons make stereotyped pathway choices to reach their targets. The initial direction of growth cone extension is probably determined by transcriptional regulators that give the cell its unique identify. Subsequent pathway choices may be controlled by cell recognition molecules that are differentially expressed on subsets of CNS axons and cell bodies. These recognition molecules may transmit information back to the cell nucleus via signal transduction pathways and thereby modify the expression of regulatory genes. Genetic evidence suggests that signal transduction via control of tyrosine phosphorylation is an important element in cell fate and axon guidance decisions. One set of molecules that re likely to be important components of these signaling pathways are four receptor-linked protein tyrosine phosphatases (R-PTPs) that are selectively expressed on CNS axons in the Drosophila embryo. These R-PTPs have extracellular domaines like those of cell adhesion molecules, and are thus good candidates for molecules that directly couple cell recognition events to signal transduction pathways within the cell. This proposal describes experiments designed to elucidate the functions of axonal R-PTPs during insect CNS development. These R-PTPs may have redundant functions during embryonic development, because mutations in two R-PTP genes do not cause visible embryonic CNS phenotypes. A mutation in a third R-PTP gene has been identified, and its embryonic CNS phenotype will be examined. In addition, two R-PTPs are expressed on distinct subsets of neuronal processes in the larval optic lobes, suggesting that they may have unique functions during optic lobe development. These functions will be explored by examining the pattern of photoreceptor synapses in the optic lobes of mutant files. A putative downstream signaling molecule for one R-PTP has been identified, and its role in PTP signaling will be explored. Ligands that interact with the extracellular domains of the R-PTPs will be identified using molecular biological or biochemical techniques. To explore the mechanisms involved in development of the embryonic CNS, a system for studying cell fate decisions in grasshopper embryo cultures will be adapted to the study of the control of axon guidance by transcription factors. It will then be used to examine in detail the functions of the R-PTPs within several neuroblast lineages.
Keywords: developmental neurobiology, molecular genetics, neurogenesis, neurogenetics, protein tyrosine phosphatase, transcription factor, chimeric protein, complementary DNA, gene mutation, growth cone, immunoglobulin G, membrane protein, neuronal guidance, nucleic acid probe, phosphoprotein, protein sequence, receptor coupling, synapse, visual photoreceptor, Drosophilidae, genetic library, laboratory mouse, larva, tissue /cell culture
Project start date: 1990-01-01
Project end date: 1999-01-31
5R01NS028182-09 (1998): $291459
5R01NS028182-08 (1997): $283418
Sponsored Links Excellgen http://Excellgen.com
MOLECULAR GENETICS OF AXON GUIDANCE
Kai G Zinn, Professor
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01NS028182-05 from National Institute Of Neurological Disorders And Stroke IRG: NEUC
Abstract: The basic architecture of a nervous system is largely determined by the pathway choices made by neuronal growth cones during embryonic development. Although the behavior of mammalian growth cones has been extensively studied in tissue culture, little is known about the molecular mechanisms by which specific pathway choices are determined in vivo. Knowledge about these mechanisms would help to explain how the mammalian nervous system develops before and after birth. This is relevant to the eventual understanding of genetic diseases that affect the structure of the brain and of sensory and motor systems. The development of the insect segmental ganglia is a good experimental system in which to isolate and study pathfinding events in vivo, because these ganglia are composed of a very small number of neurons, each of which makes a unique, genetically programmed set of pathway choices. Furthermore, the basic ganglion architecture is conserved between species suitable for cell biology studies, such as the grasshopper, and species with well-developed genetics, such as Drosophila. A variety of data suggest that individual axons or axon bundles in insect segmental ganglia are differentially labeled by surface recognition molecules that are used for growth cone guidance. The cell surface proteins known as fasciclins are good candidates for such recognition molecules. The gene encoding one of these proteins, fasciclin I, has been isolated in both grasshopper and Drosophila, and mutation in the Drosophila gene has been identified. Although this mutation alone does not cause a visible alteration of the embryonic nervous system, embryos bearing both the fasciclin I mutation and a mutation in the Drosophila homolog of the c-abl oncogene have a lethal phenotype in which the nervous system is disrupted. The nature of the description, however, is not understood. In the experiments described in this proposal, the role of fasciclin I in the development of the embryonic nervous system will be studied by analyzing in detail the phenotypes of embryos lacking both fasciclin I and abl. This will be done by examining the structure of the nervous system in double mutant embryos using light-level immunohistochemistry and electron microscopic reconstruction. Double mutant combinations will also be made with other mutations in genes encoding proteins expressed in the nervous system, and their phenotypes similarly analyzed. Potential cell-adhesion activities of fasciclin I will be studied by expressing the molecule on the surface of tissue culture cells and studying the aggregation behavior of the transformed cells. In second part of the proposal, a genetic and a biochemical method to identify other potential neuronal recognition molecules are described. In the genetic approach, new molecules that may be involved in the pathway of action of fasciclin I will be identified by screening for mutations in other genes that can be mutated to an abl -dependent lethal phenotype. The biochemical approach utilizes a monoclonal antibody against a carbohydrate moiety shared by many insect neuronal surface proteins. Two of these proteins are fasciclins; the others are presently unidentified and could include other neuronal recognition protein species will then be generated and used to isolate cDNA clones encoding them.
Keywords: axon, growth /development, nucleic acid sequence, prenatal growth disorder, CNS disorder, Drosophilidae, axon reaction, cell adhesion molecule, chromosome aberration, developmental genetics, gene expression, glycoprotein, membrane protein, molecular pathology, neural fasciculation, oncogene, protein engineering, affinity chromatography, complementary DNA, gel electrophoresis, genetic library, monoclonal antibody, mutant, tissue /cell culture, western blotting
Project start date: 1990-01-01
Project end date: 1994-12-31
5R01NS028182-05 (1994): $198734
MOLECULAR GENETICS OF AXON GUIDANCE IN THE DROSOPHILA
Kai G Zinn, Professor
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01NS028182-04 from National Institute Of Neurological Disorders And Stroke IRG: NEUC
Abstract: The basic architecture of a nervous system is largely determined by the pathway choices made by neuronal growth cones during embryonic development. Although the behavior of mammalian growth cones has been extensively studied in tissue culture, little is known about the molecular mechanisms by which specific pathway choices are determined in vivo. Knowledge about these mechanisms would help to explain how the mammalian nervous system develops before and after birth. This is relevant to the eventual understanding of genetic diseases that affect the structure of the brain and of sensory and motor systems. The development of the insect segmental ganglia is a good experimental system in which to isolate and study pathfinding events in vivo, because these ganglia are composed of a very small number of neurons, each of which makes a unique, genetically programmed set of pathway choices. Furthermore, the basic ganglion architecture is conserved between species suitable for cell biology studies, such as the grasshopper, and species with well-developed genetics, such as Drosophila. A variety of data suggest that individual axons or axon bundles in insect segmental ganglia are differentially labeled by surface recognition molecules that are used for growth cone guidance. The cell surface proteins known as fasciclins are good candidates for such recognition molecules. The gene encoding one of these proteins, fasciclin I, has been isolated in both grasshopper and Drosophila, and mutation in the Drosophila gene has been identified. Although this mutation alone does not cause a visible alteration of the embryonic nervous system, embryos bearing both the fasciclin I mutation and a mutation in the Drosophila homolog of the c-abl oncogene have a lethal phenotype in which the nervous system is disrupted. The nature of the description, however, is not understood. In the experiments described in this proposal, the role of fasciclin I in the development of the embryonic nervous system will be studied by analyzing in detail the phenotypes of embryos lacking both fasciclin I and abl. This will be done by examining the structure of the nervous system in double mutant embryos using light-level immunohistochemistry and electron microscopic reconstruction. Double mutant combinations will also be made with other mutations in genes encoding proteins expressed in the nervous system, and their phenotypes similarly analyzed. Potential cell-adhesion activities of fasciclin I will be studied by expressing the molecule on the surface of tissue culture cells and studying the aggregation behavior of the transformed cells. In second part of the proposal, a genetic and a biochemical method to identify other potential neuronal recognition molecules are described. In the genetic approach, new molecules that may be involved in the pathway of action of fasciclin I will be identified by screening for mutations in other genes that can be mutated to an abl -dependent lethal phenotype. The biochemical approach utilizes a monoclonal antibody against a carbohydrate moiety shared by many insect neuronal surface proteins. Two of these proteins are fasciclins; the others are presently unidentified and could include other neuronal recognition protein species will then be generated and used to isolate cDNA clones encoding them.
Keywords: axon, growth /development, nucleic acid sequence, prenatal growth disorder, CNS disorder, Drosophilidae, axon reaction, cell adhesion molecule, chromosome aberration, developmental genetics, gene expression, glycoprotein, membrane protein, molecular pathology, neural fasciculation, oncogene, protein engineering, affinity chromatography, complementary DNA, gel electrophoresis, genetic library, monoclonal antibody, mutant, tissue /cell culture, western blotting
Project start date: 1990-01-01
Project end date: 1994-12-31
5R01NS028182-04 (1993): $187592
5R01NS028182-03 (1992): $184068
SYNAPTIC TARGET SELECTION IN DROSOPHILA
Kai G Zinn, Professor Of Biology
California Institute Of Technology, Office Of Sponsored Research, Mail Code 201-15, Pasadena, Ca 91125
Grant 3R01NS062821-02S1 from National Institute Of Neurological Disorders And Stroke
Abstract: Synaptic target selection in Drosophila Genetic screens in Drosophila identified many of the cell-surface and secreted (CSS) proteins that are intensively studied today as regulators of axon guidance in both vertebrate and invertebrate systems. This proposal describes a genetic screen for CSS proteins that function as synaptic target labels in the embryonic/larval neuromuscular system. This system is ideal for examination of target labeling mechanisms, because it contains only 36 motor neurons and 30 muscle targets and has an invariant innervation pattern. Each identified motor neuron innervates a specific muscle fiber. Although many genes that regulate axon guidance in this system have been identified, we know very little about how individual muscle fibers are recognized as targets by motor axons. To address this problem, we first defined CSS proteins that cause axonal mistargeting when they are overexpressed on all muscle fibers. We did this by constructing a database of all genes in Drosophila that encode CSS proteins likely to be involved in cell recognition events. We then searched through all the existing collections of UAS (GAL4 binding site)-containing (´EP-like´) element lines to find insertions immediately upstream of these CSS genes that could be used to confer tissue-specific, high-level expression by crossing them to GAL4 "driver" lines. We obtained EP-like insertions that can drive 410 of the 979 genes in the database, or over 40% of the putative cell recognition repertoire. We crossed each line to a pan-muscle GAL4 driver and examined F1 progeny larvae by antibody staining and confocal microscopy. We found 30 genes whose expression on all muscles causes high-penetrance axonal mistargeting phenotypes but does not perturb muscle structure. Six of the genes are in a specific family encoding proteins with extracellular domains containing leucine-rich repeats (LRRs), which are protein interaction modules. This proposal describes experiments to assess the functions of four LRR proteins that are expressed in muscles and appear to function as synaptic target labels, and to determine if the LRR family encodes additional target labels. The first specific aim concerns the Tartan (Trn) and Capricious (Caps) proteins. Loss-of- function phenotypes for trn and caps suggest that they function in a partially redundant manner in the embryo. In larvae, selective expression of Trn or Caps on muscle 12 only produces alterations in targeting specificity. We will determine the loss-of-function (LOF) larval phenotypes generated by knockdown of both Trn and Caps in a single muscle or in all muscles. We will also attempt to develop a method for labeling single motor axons in larvae, so that we can observe how genetic perturbations affect targeting of individual identified axons. Specific aims 2 and 3 concern two "new genes", CG14351/haf and CG8561. We have used genetic and RNAi analysis to show that the proteins encoded by these genes are required for the normal innervation of ventrolateral muscles. We will make null mutations in these genes and conduct a genetic interaction screen to find components of the CG14351/Haf signaling pathway. We will also determine whether CG8561, the ortholog of a mammalian IGF-1 binding protein, is a component of the insulin/IGF-1 signaling pathway. The final specific aim describes experiments to examine the entire LRR family to determine if it encodes other muscle target labels. To do this, we will make UAS-cDNA constructs and obtain or make RNAi lines for 41 LRR genes and assess their phenotypes in larvae. For all genes producing phenotypes, we will then make a map of their expression patterns in muscle fibers during the period of axonal outgrowth. This information will allow us to begin to combine LRR protein perturbations, knocking down multiple genes on specific muscles, in order to examine whether muscle fibers are labeled for targeting by expression of specific ensembles of LRR proteins
Keywords: No Project Terms available
Relevance: Relevance to human health: This is a basic research project to discover mechanisms involved in creation of neuronal circuits during development. Although the work is conducted in Drosophila, most of the genes we are studying have human counterparts. We hope to reveal general principles that will facilitate an understanding of how human brain wiring is controlled before and after birth. Knowledge about wiring mechanisms may help researchers to understand diseases in which neuronal connectivity patterns are altered. These include schizophrenia and autism
Project start date: 2009-02-01
Project end date: 2013-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
3R01NS062821-02S1 (2010): $90720
DROSOPHILA MODEL FOR GENETICS OF OBESITY
Kai G Zinn
California Institute Of Technology, Office Of Sponsored Research, Mail Code 201-15, Pasadena, Ca 91125
Grant 3R01DK070154-04S1 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Obesity is a complex disorder caused by an imbalance between food intake and energy expenditure. These processes normally are precisely regulated, so that body weight can remain constant over a long time, in spite of variable food intake and activity. This homeostasis suggests the presence of strong regulatory mechanisms, and most biological mechanisms have an underlying genetic basis. The isolation of the Drosophila adipose mutation in the 1960´s demonstrated that Drosophila can become obese, since that mutation causes a doubling in the overall fat content of adult flies. The strength of Drosophila as an experimental organism lies not only in its amenability to large scale, fast, and cheap genetic screening, but also in many years of genetic analysis, climaxing with the complete sequence of its genome, which makes it relatively easy to identify and clone genes with interesting mutant phenotypes. The list of biological problems for which Drosophila has been used successfully as a model is impressive, including the identification of genes that regulate the circadian rhythm, aspects of behavior such as learning and memory, and nervous system development. Many of these genes have provided clues to the discovery of their mammalian homologs. The use of Drosophila in obesity research opens the prospect of large-scale genetic screens to identify genes responsible for appetite control, body weight regulation, and fat storage, as well as analysis of the underlying biological mechanisms. We have isolated a series of obese mutants of Drosophila. The specific aims of the project will be to characterize their phenotypes, clone the genes, analyze the affected biochemical pathways, and isolate suppressor genes to reverse the genetic obesity defects
Keywords: 21+ years old; Adipocytes; Adipose Cell; Adipose tissue; Adult; Affect; Appetite; Autoregulation; Behavior; Biochemical Pathway; Biological; Body Weight; Cell Count; Cell Number; Circadian Rhythms; Complex; Defect; Desire for food; Disease; Disorder; Diurnal Rhythm; Drosophila; Drosophila genus; Eating; Energy Expenditure; Energy Metabolism; Experimental Organism; Fat Cells; Fats; Fatty Tissue; Fatty acid glycerol esters; Flies; Food Intake; Fruit Fly, Drosophila; GeneHomolog; Genes; Genes, Suppressor; Genetic; Genetic Alteration; Genetic Change; Genetic Models; Genetic Screening; Genetic analyses; Genetic defect; Genome; Homeostasis; Homolog; Homologous Gene; Homologue; Human, Adult; Laboratory Organism; Learning; Lipocytes; Locomotor Activity; Mature Lipocyte; Mature fat cell; Memory; Metabolic; Metabolic Networks; Modeling; Models, Genetic; Morphology; Motor Activity; Mutation; Nyctohemeral Rhythm; Obesity; Phenotype; Physiological Homeostasis; Process; Regulation; Research; Second-Site Suppressor Genes; Series; Suppressor Genes; Time; Twenty-Four Hour Rhythm; adipose; adiposity; adult human (21+); base; circadian; circadian process; corpulence; corpulency; corpulentia; daily biorhythm; disease/disorder; diurnal variation; fly; fruit fly; gene cloning; genetic analysis; genome mutation; interest; mutant; nervous system development; obese; obese people; obese person; obese population; positional cloning; reverse genetics; white adipose tissue; yellow adipose tissue
Project start date: 2004-09-20
Project end date: 2010-08-31
Budget start date: 19-NOV-2009
Budget end date: 31-AUG-2010
PFA/PA: RFA-DK-03-018
3R01DK070154-04S1 (2010): $100934
5R01DK070154-04 (2007): $338303
DENDRITIC PROTEIN SYNTHESIS IN HIPPOCAMPAL NEURONS
Kai G Zinn
California Institute Of Technology, Office Of Sponsored Research, Mail Code 201-15, Pasadena, Ca 91125
Grant 5R01MH065537-09 from National Institute Of Mental Health
Abstract: It is now clear that protein synthesis is required for animals to establish long-term memories. Misregulation of synaptic tranmission and protein synthesis plays an important role in many diseases. Until recently, it was assumed that all of the proteins required for all neuronal function were made in the cell body. The discovery of polyribosomes at the base of neuronal synapses suggested the possibility that proteins might be synthesized in dendrites in response to synaptic activity. In the previous grant period, we focussed our attention on the development of imaging techniques to visualize protein synthesis in dendrites and discovered several forms of plasticity that are implemented by local protein synthesis. In this proposal we will examine the signaling mechanisms that couple miniature synaptic transmission (minis) to the protein translation machinery. We previously discovered that minis tonically inhibit the dendritic protein synthesis machinery. Loss of minis leads to an upregulation of translation and a rapid homeostatic response. We wish to examine which intracellular signaling pathways couple neurotransmitter receptor activation to the protein synthesis machinery. We will also determine whether there is stimulation-dependent assembly and trafficking of ribosomes in dendrites. Previous observations of ribosomes in dendrites of hippocampal neurons suggest that the translational capacity of synapses in spines is limited by the number of ribosomes available in the dendritic pool. Using biochemical approaches and dynamic time-lapse imaging, we will examine whether polyribosomes might be assembled locally in spines or trafficked to spines. One of big unanswered questions concerns the relative contributions of somatically vs. dendritic synthesized proteins to synaptic function and plasticity. Recently we have developed a technique that can be used to identify the constituents of the dendritically proteome. Building on this technology, we will modify our procedure for labelling proteins in lysates to include fluorescent labelling of proteins in intact cells and tissue slices. We will develop multiple fluorescent tags to separately track proteins made in the cell body and the dendrites.The fate of proteins synthesized in these two compartments will be analyzed over time to address the fractional contribution of somatic vs. dendritic protein synthesis to the synaptic protein population and how these contributions change with synaptic activity and plasticity
Keywords: Address; Ammon Horn; Animals; Attention; Axon; Biochemical; Biogenesis; Body Tissues; CAM kinase III; Cam PK III; Cell Body; Cell Communication and Signaling; Cell Signaling; Cells; Cornu Ammonis; Dendrites; Development; Disease; Disorder; E-2 kinase; EF-2 kinase; Funding; Grant; Hippocampus; Hippocampus (Brain); Image; Imaging Procedures; Imaging Techniques; Individual; Intracellular Communication and Signaling; Label; Methods and Techniques; Methods, Other; Microfluidic; Microfluidics; Nerve Cells; Nerve Unit; Neural Cell; Neural Transmission; Neurocyte; Neuromediator Receptors; Neurons; Neuroregulator Receptors; Neurotransmitter Receptor; Origin of Life; Pathway interactions; Peptide Biosynthesis, Ribosomal; Play; Polyribosomes; Polysomes; Population; Procedures; Process; Protein Biosynthesis; Protein Biosynthesis, Ribosomal; Protein Synthesis, Ribosomal; Proteins; Proteome; Receptor Activation; Receptors, Neurohumor; Relative; Relative (related person); Reporter; Ribosomes; Role; Sampling; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Slice; Spinal Column; Spine; Stimulus; Synapses; Synaptic; Synaptic Transmission; Technics, Imaging; Techniques; Technology; Testing; Time; Tissues; Translations; Up-Regulation; Up-Regulation (Physiology); Upregulation; Vertebral column; backbone; base; biological signal transduction; calmodulin-dependent protein kinase III; cell body (neuron); disease/disorder; eEF-2-specific Ca and calmodulin-dependent protein kinase III; elongation factor 2 kinase; gene product; hippocampal; imaging; long term memory; neural cell body; neuronal; neuronal cell body; pathway; protein kinase CPK3; protein synthesis; response; social role; soma; synapse function; synaptic function; trafficking
Project start date: 2002-06-01
Project end date: 2012-05-31
Budget start date: 28-AUG-2010
Budget end date: 31-MAY-2011
5R01MH065537-09 (2010): $267828
SYNAPTIC TARGET SELECTION IN DROSOPHILA
Kai G Zinn, Professor Of Biology
California Institute Of Technology, Office Of Sponsored Research, Mail Code 201-15, Pasadena, Ca 91125
Grant 5R01NS062821-02 from National Institute Of Neurological Disorders And Stroke
Abstract: Genetic screens in Drosophila identified many of the cell-surface and secreted (CSS) proteins that are intensively studied today as regulators of axon guidance in both vertebrate and invertebrate systems. This proposal describes a genetic screen for CSS proteins that function as synaptic target labels in the embryonic/larval neuromuscular system. This system is ideal for examination of target labeling mechanisms, because it contains only 36 motor neurons and 30 muscle targets and has an invariant innervation pattern. Each identified motor neuron innervates a specific muscle fiber. Although many genes that regulate axon guidance in this system have been identified, we know very little about how individual muscle fibers are recognized as targets by motor axons. To address this problem, we first defined CSS proteins that cause axonal mistargeting when they are overexpressed on all muscle fibers. We did this by constructing a database of all genes in Drosophila that encode CSS proteins likely to be involved in cell recognition events. We then searched through all the existing collections of UAS (GAL4 binding site)-containing (´EP-like´) element lines to find insertions immediately upstream of these CSS genes that could be used to confer tissue-specific, high-level expression by crossing them to GAL4 "driver" lines. We obtained EP-like insertions that can drive 410 of the 979 genes in the database, or over 40% of the putative cell recognition repertoire. We crossed each line to a pan-muscle GAL4 driver and examined F1 progeny larvae by antibody staining and confocal microscopy. We found 30 genes whose expression on all muscles causes high-penetrance axonal mistargeting phenotypes but does not perturb muscle structure. Six of the genes are in a specific family encoding proteins with extracellular domains containing leucine-rich repeats (LRRs), which are protein interaction modules. This proposal describes experiments to assess the functions of four LRR proteins that are expressed in muscles and appear to function as synaptic target labels, and to determine if the LRR family encodes additional target labels. The first specific aim concerns the Tartan (Trn) and Capricious (Caps) proteins. Loss-of- function phenotypes for trn and caps suggest that they function in a partially redundant manner in the embryo. In larvae, selective expression of Trn or Caps on muscle 12 only produces alterations in targeting specificity. We will determine the loss-of-function (LOF) larval phenotypes generated by knockdown of both Trn and Caps in a single muscle or in all muscles. We will also attempt to develop a method for labeling single motor axons in larvae, so that we can observe how genetic perturbations affect targeting of individual identified axons. Specific aims 2 and 3 concern two "new genes", CG14351/haf and CG8561. We have used genetic and RNAi analysis to show that the proteins encoded by these genes are required for the normal innervation of ventrolateral muscles. We will make null mutations in these genes and conduct a genetic interaction screen to find components of the CG14351/Haf signaling pathway. We will also determine whether CG8561, the ortholog of a mammalian IGF-1 binding protein, is a component of the insulin/IGF-1 signaling pathway. The final specific aim describes experiments to examine the entire LRR family to determine if it encodes other muscle target labels. To do this, we will make UAS-cDNA constructs and obtain or make RNAi lines for 41 LRR genes and assess their phenotypes in larvae. For all genes producing phenotypes, we will then make a map of their expression patterns in muscle fibers during the period of axonal outgrowth. This information will allow us to begin to combine LRR protein perturbations, knocking down multiple genes on specific muscles, in order to examine whether muscle fibers are labeled for targeting by expression of specific ensembles of LRR proteins. This is a basic research project to discover mechanisms involved in creation of neuronal circuits during development. Although the work is conducted in Drosophila, most of the genes we are studying have human counterparts. We hope to reveal general principles that will facilitate an understanding of how human brain wiring is controlled before and after birth. Knowledge about wiring mechanisms may help researchers to understand diseases in which neuronal connectivity patterns are altered. These include schizophrenia and autism
Keywords: AFBP; Address; Affect; Alpha-Pregnancy-Associated Endometrial Globulin; Amniotic Fluid Binding Protein; Antibodies; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Axon; Back; Basic Research; Basic Science; Binding Protein-25; Binding Protein-26; Binding Protein-28; Binding Sites; Birth; Body Tissues; Brain; Cell surface; Cells; Chimp; Chimpanzee; Collection; Combining Site; Complementary DNA; Complex; Confocal Microscopy; Cues; DNA, Complementary; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Development; Disease; Disorder; Dorsum; Drosophila; Drosophila genus; EC 2.7; Elements; Embryo; Embryonic; Encephalon; Encephalons; Event; External Domain; Extracellular Domain; Family; Fruit Fly, Drosophila; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic Screening; Genetic defect; Growth Hormone Independent-Binding Protein; Health; Human; Human, General; Humulin R; IBP-1; IGF-1 Receptor; IGF-1 Signaling Pathway; IGF-Binding Protein 1; IGF1R; IGFBP-1; IGFBP1; Individual; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin Signaling Pathway; Insulin, Regular; Insulin-Like Growth Factor 1 Receptor; Insulin-Like Growth-Factor Binding Protein 1; Insulin-Like-Growth Factor I Receptor; Invertebrata; Invertebrates; Invertebrates, General; Investigators; Kanner`s Syndrome; Kinases; Knowledge; LRR; LRR protein; Label; Larva; Leucine-Rich Repeat; Link; Man (Taxonomy); Man, Modern; Maps; Methods; Microscopy, Confocal; Motor; Motor Cell; Motor Neurons; Muscle; Muscle Fibers; Muscle Tissue; Mutation; Myoneural Junction; Myotubes; Nature; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; Neuromuscular Junction; Neurons; Novolin R; Ortholog; Orthologous Gene; PP12; Pan; Pan Genus; Pan Species; Paper; Parturition; Pattern; Penetrance; Phenotype; Phosphotransferases; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Protein Family; Proteins; Quelling; R01 Mechanism; R01 Program; RNA Interference; RNA Silencing; RNA Silencings; RNAi; RPG; Reactive Site; Receptor Protein; Receptor, IGF Type 1; Receptor, IGF-I; Receptor, Insulin-Like Growth Factor Type 1; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Researchers; Rhabdomyocyte; Right-Handed Beta-Alpha Superhelix; Schizophrenia; Schizophrenic Disorders; Sequence-Specific Posttranscriptional Gene Silencing; Signal Pathway; Skeletal Fiber; Skeletal Muscle Cell; Skeletal Muscle Fiber; Skeletal Myocytes; Specificity; Staining method; Stainings; Stains; Synapses; Synaptic; System; System, LOINC Axis 4; Tissues; Transphosphorylases; Work; ing; axon growth cone guidance; axon guidance; cDNA; clinical data repository; clinical data warehouse; data repository; dementia praecox; disease/disorder; experiment; experimental research; experimental study; fruit fly; gain of function; gene product; genome mutation; innervation; insulin signaling; interest; knock-down; leucine-rich repeat protein; loss of function; member; motoneuron; muscular structure; nerve supply; neuromotor system; neuromuscular system; neuronal; null mutation; overexpression; placental protein 12; postsynaptic; protein function; receptor; relational database; research study; schizophrenic; selective expression; selectively expressed
Relevance: Relevance to human health: This is a basic research project to discover mechanisms involved in creation of neuronal circuits during development. Although the work is conducted in Drosophila, most of the genes we are studying have human counterparts. We hope to reveal general principles that will facilitate an understanding of how human brain wiring is controlled before and after birth. Knowledge about wiring mechanisms may help researchers to understand diseases in which neuronal connectivity patterns are altered. These include schizophrenia and autism
Project start date: 2009-02-01
Project end date: 2014-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
5R01NS062821-02 (2010): $347584
Sponsored Links Excellgen http://Excellgen.com
Kai G Zinn
California Institute Of Technology
Project start date: 1990-01-01
Project end date: 2013-11-30
MOLECULAR GENETICS OF CNS DEVELOPMENT
Kai G Zinn
Department/ Educational Institution Type:
Grant 5R01NS028182-22 from National Institute Of Neurological Disorders And Stroke
Keywords: ing; Active Follow-up; Affect; Apical; apical membrane; Assay; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Axon; axon growth cone guidance; axon guidance; balance; balance function; base; Basic Research; Basic Science; Binding; Binding (Molecular Function); Binding Proteins; Bioassay; Biochemical Genetics; Biologic Assays; Biological Assay; biological signal transduction; Birth; Brain; c-erbB-1; c-erbB-1 Protein; Cell Communication and Signaling; Cell Culture Techniques; Cell Signaling; Cell surface; Cell Surface Proteins; Cells; Chimera Protein; Chimeric Proteins; Cytosolic Protein Tyrosine Phosphastase; Data; dementia praecox; Dephosphorylation; Development; Disease; disease/disorder; Disorder; Drosophila; Drosophila genus; Ectopic Expression; EGFR; Embryo; embryo cell; embryo protein; Embryonic; embryonic protein; Encephalon; Encephalons; Endocytic Vesicle; Endocytosis; Endocytotic Vesicle; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Equilibrium; ERBB Protein; erbB-1; erbB-1 Proto-Oncogene Protein; ERBB1; erbBl; Exocytosis; Family; follow-up; fruit fly; Fruit Fly, Drosophila; Funding Agency; Funding Source; Fusion Protein; gene discovery; gene function; gene product; Generations; Genes; Genetic; Genetic Alteration; Genetic analyses; genetic analysis; Genetic Change; Genetic defect; Genetic Screening; Genetic, Biochemical; Genome; genome mutation; Glia; Glial Cells; Grant; GTP Phosphohydrolases; GTPases; Guanosine Triphosphate Phosphohydrolases; guanosinetriphosphatase; Guanosinetriphosphatases; Health; HER1; Human; Human, General; in vivo; insight; Integral Membrane Protein; Intracellular Communication and Signaling; Intrinsic Membrane Protein; Investigators; Kanner`s Syndrome; Knowledge; Kolliker`s reticulum; L-Tyrosine; Ligand Binding Protein; Ligands; Man (Taxonomy); Man, Modern; Mass Spectrum; Mass Spectrum Analysis; member; Methods; Modification; Molecular; Molecular Genetic; Molecular Genetics; Molecular Interaction; Motor; mutant; Mutation; Nerve Cells; nerve cement; Nerve Unit; Nervous System; Nervous system structure; Nervous System, Brain; Neural Cell; Neurocyte; Neuroglia; Neuroglial Cells; Neurologic Body System; Neurologic Organ System; neuronal; Neurons; new approaches; Non-neuronal cell; novel approaches; novel strategies; novel strategy; NRVS-SYS; Orphan; para-Tyrosine; Parturition; pathway; Pathway interactions; Pattern; Phenotype; Phosphorylation; Phosphotyrosine Phosphatase; Phosphotyrosyl Protein Phosphatase; Photometry/Spectrum Analysis, Mass; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Protein Binding; Protein Dephosphorylation; Protein Phosphorylation; Protein Trafficking; protein transport; Protein Tyrosine Phosphatase; protein tyrosine phosphate phosphohydrolase; Proteins; proto-oncogene protein c-erbB-1; PTPase; Quelling; R01 Mechanism; R01 Program; rab G-Proteins; rab GTP-Binding Proteins; rab GTPases; receptor; receptor function; Receptor Protein; Receptor, EGF; Receptor, TGF-alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Regulation; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Researchers; rho; RNA Interference; RNA Silencing; RNA Silencings; RNAi; Role; RPG; Schizophrenia; schizophrenic; Schizophrenic Disorders; screening; Screening procedure; screenings; Sequence-Specific Posttranscriptional Gene Silencing; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; social role; Spectrometry, Mass; Spectroscopy, Mass; Spectrum Analyses, Mass; Spectrum Analysis, Mass; Staining method; Stainings; Stains; Surface; synapse formation; Synapses; Synaptic; synaptogenesis; syndecan; Trachea; Trachea Proper; Traffickings, Protein; Transforming Growth Factor alpha Receptor; Transmembrane Protein; Tube; TYR; Tyrosine; Tyrosine Phosphatase; Tyrosine, L-isomer; Tyrosyl Phosphoprotein Phosphatase; Vacuole; windpipe; Work
Relevance: Relevance to human health: This is a basic research project to discover mechanisms involved in creation of neuronal circuits during development. Although the work is conducted in Drosophila, most of the genes we are studying have human counterparts. We hope to reveal general principles that will facilitate an understanding of how human brain wiring is controlled before and after birth. Knowledge about wiring mechanisms may help researchers to understand diseases in which neuronal connectivity patterns are altered. These include schizophrenia and autism
Project start date: 1990-01-01
Project end date: 2013-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01NS028182-22 (2011): $309340
5R01NS028182-21 (2010): $340275
MOLECULAR ANALYSIS OF OLFACTORY SIGNAL TRANSDUCTION
Kai G Zinn, Professor
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5P50MH049176-100002 from National Institute Of Mental Health
PREDOCTORAL TRAINING IN BIOLOGY AND BIOPHYSICS
Kai G Zinn, Professor
California Institute Of Technology
office Of Sponsored Research, Mail Code 201-15
pasadena, Ca 91125
Grant 5T32GM007737-20 from National Institute Of General Medical Sciences IRG: SRC
Project start date: 1979-07-01
Project end date: 1999-06-30
5T32GM007737-20 (1998): $215527
5T32GM007737-19 (1997): $338607
MOLECULAR GENETICS OF CNS DEVELOPMENT
Kai G Zinn, Professor
California Institute Of Technology Office Of Sponsored Research, Mail Code 201-15 Pasadena, Ca 91125
Grant 5R01NS028182-07 from National Institute Of Neurological Disorders And Stroke IRG: NEUC
Project start date: 1990-01-01
Project end date: 1999-01-31
5R01NS028182-07 (1996): $280179