Impact of the Xenopus system on the missions of the NINDS
Darcy B. Kelley, Ph.D.- Columbia University
The mission of the NINDS is to reduce the burden of neurological disease.� This mission is supported by a robust portfolio of basic research efforts aimed at understanding the structure and activities of the brain, knowledge essential for diagnosing and treating human brain disease. Some important areas of NINDS basic research include: biology of the cells of the nervous system, brain and nervous system development, genetics of the brain, cognition and behavior, neurodegeneration, brain plasticity and repair, neural signaling, learning and memory, motor control and integration, sensory function, and neural channels, synapses, and circuits.�
As an overview, because of the ease with which its developing and adult nervous system can be studied, Xenopus has been an important model system for understanding brain function. Among the most prominent early examples of general biological insights were Gurdon's studies demonstrating that a cell nucleus from embryonic intestine could drive development of an entire embryo, using nuclear transplantation at the one-cell stage1.� The use of informative (e.g. animal cap) assays for early tissues interactions (induction) demonstrated that this model system is an engine for gene discovery in neural development2. Important insights into synapse formation and refinement came from studies of neuromuscular junctions, especially those in very early development3 and from the establishment of topographic maps in the retinotectal system4.� Our understanding of ion channel function in the nervous system has been heavily dependent on expression in Xenopus oocytes5.� Neuroendocrine discoveries included the identification and isolation of melanocyte stimulating hormone6. These historical strengths have been followed by a series of very important new discoveries, falling within the NINDS mission, whose insights would have been much more difficult, or impossible, to obtain with other systems.� Selected examples from the recent literature (2006 � 2009) are given below.
The fundamental contributions of research in Xenopus is documented in the recent papers listed below that were selected to illustrate the facilitation of NINDS mission objectives through use of this model system.� The topics range widely and the contributions are substantive and highly visible.
Cell biology of neurons
Agathocleous Michalis; Iordanova Ilina; Willardsen Minde I; Xue Xiao Yan; Vetter Monica L; Harris William A; Moore Kathryn B� �A directional Wnt/beta-catenin-Sox2-proneural pathway regulates the transition from proliferation to differentiation in the Xenopus retina.� Development (Cambridge, England)� (2009),� 136(19),� 3289-99.�
Bollmann Johann H; Engert Florian� �Subcellular topography of visually driven dendritic activity in the vertebrate visual system.� Neuron� (2009),� 61(6),� 895-905.
W. Shen, J.S. Da Silva, H. He and Hollis T. Cline Type A GABA-receptor-dependent synaptic transmission sculpts dendritic arbor structure in Xenopus tadpoles in vivo. (2009) J Neurosci. 29:5032-43.
Bertolesi GE, Michaiel G, McFarlane S. Two heparanase splicing variants with distinct properties are necessary in early Xenopus development.� J Biol Chem. (2008) 283:16004-16
Carlos Carmona-Fontaine, Helen K. Matthews, Sei Kuriyama, Mauricio Moreno, Graham A. Dunn2, Maddy Parsons2, Claudio D. Stern1 and Roberto Mayor� Contact inhibition of locomotion in vivo controls neural crest directional migration. �Nature (2008) 456:957-961.
Ly Alice; Nikolaev Anatoly; Suresh Geetha; Zheng Yufang; Tessier-Lavigne Marc; Stein Elke� DSCAM is a netrin receptor that collaborates with DCC in� mediating turning responses to netrin - 1.� Cell� (2008) 133: 1241-54.
Green Jeremy B A; Davidson Lance A� �Convergent extension and the hexahedral cell.��� Nature cell biology� (2007) 9: 1010-5.
Mitchell Brian; Jacobs Richard; Li Julie; Chien Shu; Kintner Chris� �A positive feedback mechanism governs the polarity and motion of motile cilia.� Nature� (2007),� 447: 97-101.
Nervous system development
Strate Ina; Min Tan H; Iliev Dobromir; Pera Edgar M� �Retinol dehydrogenase 10 is a feedback regulator of retinoic acid signalling during axis formation and patterning of the central nervous system.��� Development� (2009) 136:� 461-72.
Linda W. Chang and Nicholas C. Spitzer Spontaneous calcium spike activity in embryonic spinal neurons is regulated by developmental expression of the Na+, K+-ATPase β3 subunit. (2009) J Neurosci. 29:7877-85.
N. Bardine, C. Donow, B. Korte, A.J. Durston, W. Kn�chel and S.A. Wacker Two Hoxc6 transcripts are differentially expressed and regulate primary neurogenesis in Xenopus laevis. (2009) Dev Dyn. 238:755-65.
Denver, Robert J.; Hu, Fang; Scanlan, Thomas S.; Furlow, J. David.� �Thyroid hormone receptor subtype specificity for hormone-dependent� neurogenesis� in Xenopus laevis.��� Developmental Biology (2009) 326: 155-168.
Hassenkl�ver T, Schwartz P, Schild D, Manzini I. Purinergic signaling regulates cell proliferation of olfactory epithelium progenitors. Stem Cells. (2009) 27:2022-31.
CNS genetics; Xenopus models of neurological disease
Tam Beatrice M; Moritz Orson L� �Dark rearing rescues P23H� rhodopsin -induced retinal degeneration in a transgenic Xenopus laevis model of retinitis pigmentosa: a chromophore-dependent mechanism characterized by production of N-terminally truncated mutant� rhodopsin.��� The Journal of Neuroscience (2007),� 27(34),� 9043-53
Barela Arthur J; Waddy Salina P; Lickfett Jay G; Hunter Jessica; Anido Aimee; Helmers Sandra L; Goldin Alan L; Escayg Andrew� �An� epilepsy� mutation in the sodium channel SCN1A that decreases channel excitability.��� The Journal of Neuroscience (2006),� 26(10),� 2714-23.
Cognition and behavior; neuroendocrine regulation
Davide Dulcis �and Nicholas C. Spitzer� Illumination controls differentiation of dopamine neurons regulating behaviour. Neuron (2009) 64, 240-250.
Hu, F., Crespi, E.J. and Denver, R.J. (2008) Programming neuroendocrine stress axis activity by exposure to glucocorticoids during postembryonic development of the frog Xenopus laevis. Endocrinology 149:5470-5481.
Elliott Taffeta M; Kelley Darcy B� �Male� discrimination of receptive and unreceptive female calls by temporal features.��� The Journal of experimental biology� (2007) 210:� 2836-42.
Vignal C, Kelley D. Significance of temporal and spectral acoustic cues for sexual recognition in Xenopus laevis. Proc Biol Sci. (2007) 274:479-88.
Yang Eun-Jin; Nasipak Brian T; Kelley Darcy B� �Direct action of gonadotropin in brain integrates behavioral and reproductive functions.��� Proceedings of the National Academy of Sciences of the United States of America� (2007) 104: 2477-82.
Crespi, E.J. and Denver, R.J. Leptin (ob gene) of the South African clawed frog Xenopus laevis. Proceedings of the National Academy of Sciences, USA (2006) 103:10092-10097.
Neurodegeneration
Mazabrand, A. and Pollet N. Reduced levels of survival motor neuron protein leads to aberrant motoneuron growth in a Xenopus model of muscular atrophy.� Neurogenetics. (2009) Jun 11. DOI 10.1007/s10048-009-0200-6
Waters Michael F; Minassian Natali A; Stevanin Giovanni; Figueroa Karla P; Bannister John P A; Nolte Dagmar; Mock Allan F; Evidente Virgilio Gerald H; Fee Dominic B; Muller Ulrich; Durr Alexandra; Brice Alexis; Papazian Diane M; Pulst Stefan M� �Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes.� Nature genetics� (2006),� 38(4),� 447-51.
Boorse, G.C., Kholdani, C.A., Seasholtz, A.F. and Denver, R.J. Corticotropin-releasing factor is cytoprotective in Xenopus tadpole tail: Integration of ligand, receptor and binding protein in tail muscle cell survival. Endocrinology (2006) 147:1498-1507.
Plasticity and repair
Bonett, R.M., Hu, F., Bagamasbad, P. and Denver, R.J. Stressor and glucocorticoid-dependent induction of the immediate early gene Kr�ppel-like factor 9: implications for neural development and plasticity. Endocrinology (2009)� 150:1757�1765.
Chiu Shu-Ling; Chen Chih-Ming; Cline Hollis T� �Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo.��� Neuron� (2008),� 58(5),� 708-19.
Pineda Ricardo H; Ribera Angeles B� �Dorsal - ventral� gradient for neuronal plasticity in the embryonic spinal cord.��� The Journal of neuroscience (2008),� 28(14),� 3824-34.
Kumar Anoop; Godwin James W; Gates Phillip B; Garza-Garcia A Acely; Brockes Jeremy P� �Molecular�� basis� for the� nerve�� dependence� of limb regeneration in an adult vertebrate.��� Science (New York, N.Y.)� (2007),� 318(5851),� 772-7.
Neural signalling
X.F. Liu, P.K. Tari and K Haas K. PKM zeta restricts dendritic arbor growth by filopodial and branch stabilization within the intact and awake developing brain. (2009) J Neurosci. 29:12229-35.
N. Schwartz, A. Schohl and Edward S. Ruthazer Neural activity regulates synaptic properties and dendritic structure in vivo through calcineurin/NFAT signaling. (2009) Neuron 62:655-69.
Nishiyama Makoto; von Schimmelmann Melanie J; Togashi Kazunobu; Findley William M; Hong Kyonsoo� Membrane� potential� shifts� caused by diffusible� guidance� signals� direct� growth - cone�� turning.� Nature neuroscience� (2008) 11:� 762-71
Sharon B. Sann, Lin Xu, Hiroshi Nishimune, Joshua R. Sanes and Nicholas C. Spitzer Neurite outgrowth and in vivo sensory innervation mediated by a CaV2.2 � laminin β2 stop signal. (2008)� J. Neurosci. 28: 2366-2374.
Nicol Xavier; Voyatzis Sylvie; Muzerelle Aude; Narboux-Neme Nicolas; Sudhof Thomas C; Miles Richard; Gaspar Patricia� �cAMP�� oscillations� and� retinal�� activity�� are ��permissive� for� ephrin�� signaling�� during� the� establishment� of the retinotopic map.��� Nature neuroscience� (2007),� 10(3),� 340-7.
Learning and memory
Du JL, Wei HP, Wang ZR, Wong ST, Poo MM. Long-range retrograde spread of LTP and LTD from optic tectum to retina Proc Natl Acad Sci U S A. (2009) Nov 3. [Epub ahead of print]PMID: 19887635
R.C. Ewald and Hollis T Cline Cloning and phylogenetic analysis of NMDA receptor subunits NR1, NR2A and NR2B in Xenopus laevis tadpoles.� (2009) Front Mol Neurosci. 2:4
Maguschak, Kimberly A.; Ressler, Kerry J.� β -catenin is required for memory consolidation.��� Nature Neuroscience� (2008) 11:� 1319-1326
Motor control and integration
Dong W, Lee RH, Xu H, Yang S, Pratt KG, Cao V, Song YK, Nurmikko A, Aizenman CD. Visual avoidance in Xenopus tadpoles is correlated with the maturation of visual responses in the optic tectum. J Neurophysiol. (2009)10:803-15.
Soffe Stephen R; Roberts Alan; Li Wen-Chang� �Defining the excitatory neurons that drive the locomotor rhythm in a simple vertebrate: insights into the origin of reticulospinal control.��� The Journal of physiology� (2009),� 587(Pt 20),� 4829-44.
Zornik Erik; Kelley Darcy B� �Regulation of respiratory and vocal motor pools in the isolated brain of Xenopus laevis.��� Journal of Neuroscience (2008),� 28(3),� 612-21
Rhodes, Heather J.; Yu, Heather J.; Yamaguchi, Ayako.� �Xenopus vocalizations are controlled by a sexually differentiated hindbrain central pattern generator.��� Journal of Neuroscience� (2007),� 27(6),� 1485-1497.
Sensory function
Chen TW, Lin BJ, Schild D. Odor coding by modules of coherent mitral/tufted cells in the vertebrate olfactory bulb. Proc Natl Acad Sci U S A. (2009)106:2401-6.
Garcia-Morales Carla; Liu Chiung-Hui; Abu-Elmagd Muhammad; Hajihosseini Mohammad K; Wheeler Grant N� �Frizzled - 10� promotes sensory neuron development in Xenopus embryos.��� Developmental biology� (2009),� 335(1),� 143-55
Rossi, Christy Cortez; Hernandez-Lagunas, Laura; Zhang, Chi; Choi, Irene F.; Kwok, Letitia; Klymkowsky, Michael; Bruk Artinger, Kristin.� �Rohon - Beard� sensory neurons are induced by BMP4 expressing non-neural ectoderm in Xenopus laevis.��� Developmental Biology�� (2008),� 314(2),� 351-361.
Elliott Taffeta M; Christensen-Dalsgaard Jakob; Kelley Darcy B� �Tone� and� call� responses of units in the auditory nerve and dorsal medullary nucleus of Xenopus laevis.��� Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology� (2007),� 193(12),� 1243-57.
Channels
Bosmans Frank; Martin-Eauclaire Marie-France; Swartz Kenton J� �Deconstructing voltage sensor function and pharmacology in sodium channels.��� Nature� (2008),� 456(7219),� 202-8.
Keith, Ryan K.; Poage, Robert E.; Yokoyama, Charles T.; Catterall, William A.; Meriney, Stephen D..� �Bidirectional modulation of transmitter release by calcium channel/syntaxin interactions in vivo.��� Journal of Neuroscience� (2007),� 27(2),� 265-269.
Ben-Chaim Yair; Chanda Baron; Dascal Nathan; Bezanilla Francisco; Parnas Itzchak; Parnas Hanna� �Movement of 'gating charge' is coupled to ligand binding in a G-protein-coupled receptor.��� Nature� (2006),� 444(7115),� 106-9.
Synapses
Berghuis Paul; Rajnicek Ann M; Morozov Yury M; Ross Ruth A; Mulder Jan; Urban Gabriella M; Monory Krisztina; Marsicano Giovanni; Matteoli Michela; Canty Alison; Irving Andrew J; Katona Istvan; Yanagawa Yuchio; Rakic Pasko; Lutz Beat; Mackie Ken; Harkany Tibor� �Hardwiring the brain: endocannabinoids shape neuronal connectivity.��� Science� (2007),� 316(5828),
Xu, Chun; Zhao, Man-xia; Poo, Mu-ming; Zhang, Xiao-hui.� �GABAB receptor activation mediates frequency-dependent plasticity of developing GABAergic synapses.��� Nature Neuroscience� (2008),� 11(12),� 1410-1418
Borodinsky, Laura N.; Spitzer, Nicholas C..� �Activity-depending neurotransmitter-receptor matching at the neuromuscular junction.��� Proceedings of the National Academy of Sciences of the United States of America� (2007),� 104(1),� 335-340.
Circuits
Dunfield Derek; Haas Kurt� �Metaplasticity� governs natural experience-driven plasticity of nascent embryonic brain circuits.��� Neuron� (2009),� 64(2),� 240-50
Ramdya P, Engert F. Emergence of binocular functional properties in a monocular neural circuit. Nat Neurosci. (2008) 11:1083-90.
Pratt Kara G; Dong Wei; Aizenman Carlos D� �Development and spike timing-dependent plasticity of recurrent excitation in the Xenopus optic tectum.��� Nature neuroscience� (2008) 11:� 467-75.
Technical innovation
�Berndt, Andre; Yizhar, Ofer; Gunaydin, Lisa A.; Hegemann, Peter; Deisseroth, Karl.� �Bi - stable� neural state switches.��� Nature Neuroscience� (2009),� 12(2),� 229-234
Viczian Andrea S; Solessio Eduardo C; Lyou Yung; Zuber Michael E� �Generation of functional eyes from pluripotent cells.��� PLoS biology� (2009),� 7(8); PubMed ID 19688031
Butts, Christopher A.; Xi, Jin; Brannigan, Grace; Saad, Abdalla A.; Venkatachalan, Srinivasan P.; Pearce, Robert A.; Klein, Michael L.; Eckenhoff, Roderic G.; Dmochowski, Ivan J.� �Identification of a fluorescent general anesthetic, 1- aminoanthracene.��� Proceedings of the National Academy of Sciences of the United States of America� (2009),� 106(16),� 6501-6506.
Junek Stephan; Chen Tsai-Wen; Alevra Mihai; Schild Detlev� �Activity�� correlation�� imaging : visualizing function and structure of neuronal populations.��� Biophysical journal� (2009),� 96(9),� 3801-9
Xenopus Grants funding by the NINDS
According to NIH RePORTER Search Tool, in the fiscal year of 2009, the National Institute of Neurological Disorders & Strokes (NINDS) funded 46 grants for projects involving Xenopus. These grants total $11,306,510.� See appendix for a complete list.
2009 Xenopus White Paper � Community Needs
Executive Summary
Xenopus - a crucial model organism for biomedical research:
Experiments in model animals are a cornerstone of biomedical research and have a massive impact on our understanding of human health and disease.� The frog, Xenopus, is a widely used and crucial vertebrate model organism that offers a unique combination of three powerful advantages:� strong conservation of essential biological mechanisms, a remarkable experimental repertoire, and unparalleled cost-effectiveness when compared to murine or other mammalian models.�
In fact, for many experimental applications, Xenopus is the only viable model system.� For example, in cell and molecular biology, Xenopus extracts allow for individual components of the cell cycle or DNA replication/repair machinery to be analyzed in a manner that cannot be recapitulated in vivo or in cell culture.� For developmental biology, no other model system allows for high-throughput genomic/proteomic screening and at the same time allows for transplant/explant analysis (i.e. �experimental embryology�).� The Xenopus oocyte is unique as a system for studying channel physiology using the patch-clamp and as a system for protein expression.� Finally, Xenopus is the only vertebrate model that readily produces enough biological material for biochemical purification from eggs, intact embryos, or isolated embryonic tissues.� The combination of these characteristics offers a wide range of experimental opportunities for studies using the Xenopus system in contrast to other vertebrates such as the mouse or zebrafish.
NIH Investment in Xenopus:
����������� The NIH has made a substantial and continuing investment in Xenopus research.� Indeed, a search of the NIH rePORT database for R01�s or equivalent grants using the search term �Xenopus� returned 427 grants for a total cost of $127,583,776 for FY08 and FY09.� Despite this investment in individuals� research, the Xenopus community lacks many resources that are considered entirely essential for other model systems, including a complete genome sequence, stock and training centers, and a comprehensive model organism database.
Xenopus as a Model System and Human Disease:
Given the tremendous advantages of the Xenopus system, the pace of new biological discovery by the Xenopus Community is brisk.� Using Xenopus, we have significantly improved our understanding of human disease genes and their mechanisms, justifying the NIH�s investment in Xenopus.� Below we provide examples of just a few of the human health discoveries made in the last two years:
Xenopus embryos are used for in vivo analysis of gene expression and function:
Nephronophthisis - Hum Mol Genet. 2008. 17, 3655-62; Nat Genet. 2005. 37, 537-43.
Cutis laxa - Nat Genet. 2009. 41, 1016-21.
Meckel-Gruber syndrome - Am J Hum Genet. 2008. 82, 959-70.
Colorectal cancer - Genome Res. 2009.� 19, 987-93.
Xenopus egg extracts are used for in vitro biochemical studies:
Fanconi Anemia - Mol. Cell. 2009. 35, 704-15;� J Biol Chem. 2009, 284, 25560-8.
C-myc oncogene - Nature. 2007. 448, 445-51.
BRCA1 - Cell. 2006. 127, 539-552
Xenopus oocytes are used to study gene expression and channel activity:
Trypanosome transmission - Nature 2009. 459, 213-217.
Epilepsy, ataxia, sensorineural deafness - N Engl J Med. 360, 1960-70.
Catastrophic cardiac arrhythmia (Long-QT syndrome) - PNAS �2009. 106,13082-7.
Megalencephalic leukoencephalopathy - Hum Mol Genet. 2008. 17, 3728-39.
Xenopus as a Model System and Basic Biological Processes:
Xenopus also plays a crucial role in elucidating the basic cellular and biochemical mechanisms underlying the entire spectrum of human pathologies.� Again only a few of the many discoveries in the last two years are highlighted here:
Xenopus embryos were used for studies of TGF-� signal transduction.
(Cell. 2009. 136,123-35; Science. 2007. 315, 840-3).
Xenopus egg extracts revealed fundamental aspects of cell division.
(Nature. 2008. 453, 1132-6; Science. 2008. 319, 469-72).
Xenopus embryos were used for studying mucociliary epithelia.
(Nat Genet. 2008. 40, 871-9; Nature. 2007. 447, 97-101).
Xenopus embryos were used for studying development of the vasculature.
(Cell. 2008.135, 1053-64).
Xenopus egg extracts provided key insight into DNA damage responses. �
(Mol Cell.� 2009. 35,704-15; Cell. 2008. 134, 969-80).
Xenopus embryos linked telomerase to Wnt signaling.
(Nature. 2009. 460, 66-72).
Xenopus was used for small molecule screens to develop therapeutics.
(Nat Chem Biol. 2008. 4, 119-25; Blood. 2009. 114, 1110-22).
Immediate Needs of the Xenopus Community:
����������� It is the consensus of the Xenopus community that their biomedical research could be greatly accelerated by the development of key resources that are currently lacking.� These resources would be of use to the entire Xenopus research community.� In this White Paper, the community identifies seven resources in two categories: Three Immediate Needs and four Essential Resources:
The Immediate Needs are a common set of key resources that were identified as the most pressing by three committees established to identify needed resources across the broad and diverse Xenopus community.� There is a broad, community-wide consensus that these resources would have an immediate impact on all Xenopus users and should be assigned the highest priority in order to accelerate the pace of biomedical research using Xenopus as a model system.�
����������� These Immediate Needs and the resulting improvements in biomedical research are as follows:
1.� Establishment of the Xenopus Resource and Training Center at the MBL in Woods Hole.
-Will allow rapid distribution of transgenic Xenopus laevis lines expressing fluorescent reporters and tagged proteins (for example histone-RFP for visualizing the mitotic spindle or organ specific GFP in embryos)
-Will allow centralized generation, housing, and distribution of genetically modified X. tropicalis lines, including both mutants and transgenics.
-Will allow both current investigators and the next generation of researchers to get hands-on training in� Xenopus-based biomedical research methods (including cell, molecular, and developmental methods).
2.� Expansion and improvement of Xenbase, a Xenopus model organism database.
-Maintain and curate data for the essential primary database for Xenopus researchers.
-Enhance the functionality of Xenbase by introducing a phenotypes feature.
-Support new content on Xenbase, including proteomics support, a new genome browser, and Wiki for Xenopus methods.
-Continue and expand collaborative and service efforts (e.g. provide Xenopus data to other databases including NCBI, UniProtK, Mascot and Tornado).
3.� Complete sequencing of the Xenopus laevis genome.
-Will allow the deconvolution of data in mass-spectrometry-based proteomic studies.
-Will facilitate identification of conserved gene regulatory regions to build gene-regulatory networks.
-Will facilitate site-specifc studies of DNA transaction (repair and replication)
-Will facilitate identification of all ORFs to build an ORFeome for rapid functional characterization of genes
-Will facilitate the design of morpholino oligonucleotides for gene depletion studies
-Will faciliate the analysis of chromatin-immunoprecipitations to identify DNA-bound to transcription factors and DNA modifications.
Essential Resources Needed by the Xenopus Community:
����������� In addition to these immediate, community-wide needs, the committees identified four Essential Resources that should be developed as soon as possible, so that Xenopus biologists can more effectively fulfill the missions of the NIH.� The Xenopus community considers all four of these additional resources to be essential, but understands that priorities must be set, and ranks these behind the Immediate Needs. These Essential Resources are as follows:
4.� Xenopus ORFeome in recombineering vectors.��
5.� Improvement of the X. tropicalis genome sequence and annotation
6.� Development of methods for disrupting gene function in Xenopus.
7. �Generation and Distribution of antibodies for Xenopus research.
Anticipated Gains for Biomedical Research:
����������� Xenopus is a crucial model organism for biomedical research.� With the development of large-scale community-wide resources, Xenopus is poised to be become the premier vertebrate model for systems-level approaches to understanding biological mechanisms in cell, molecular, and developmental biology.
The National Research Council and the National Academy of Sciences have recently called on the Unites States �to launch a new multiagency, multiyear, and multidisciplinary initiative to capitalize on the extraordinary advances recently made in biology�.� This report (http://www.nap.edu/catalog.php?record_id=12764) recommends the term "new biology" to describe an approach to research where �physicists, chemists, computer scientists, engineers, mathematicians, and other scientists are integrated into the field of biology.�� The promise of systems-level analysis in Xenopus, combined with its already proven strengths, make Xenopus the ideal model organism for pursuing this �new biology.�
Genome improvements will provide Xenopus researchers with the ability to perform genome-wide screens for biological activities that will in turn allow the rapid assembly and analysis of gene regulatory networks.� The ORFeome will greatly facilitate such genome-wide screening by allowing all ORFs to be rapidly analyzed or large numbers of proteins to be tagged for analysis of protein-protein interaction or for in vivo visualization.� Using extracts and biochemical purification coupled with mass-spectrometry and genomic sequence, protein interactomes can be rapidly identified and validated.� Because Xenopus can be so easily manipulated and because vast amounts of biological material can be generated, cell-type specific interactomes can also be identified.� Large-scale genetic screens will identify important novel genes in developmental pathways, especially given the relatively simple genome of X. tropicalis compared to zebrafish.� Finally, the flexibility of both Xenopus extracts and embryos make this system ideal for chemical biology screens.� Identifying these gene-regulatory networks, interactomes, and novel genes will be only the first steps, of course.� The well-established power of Xenopus for rapid analysis of gene function will then allow deeply mechanistic analyses to complement the systems-level approaches described above.�
It is the combination of these characteristics that distinguishes Xenopus from other vertebrate model systems such as mouse and zebrafish and allows for a systems-level approach to understanding biological mechanisms.� The tremendous promise of the Xenopus model cannot be realized, however, without the immediate development of community-wide research resources.� This White Paper presents the needed resources, and we look to the NIH for guidance in how to best achieve these goals.�
For complete details of the 2009 Xenopus White Paper, please visit
Appendix
Xenopus Grants funded by the NINDS
|
Project Number |
Activity |
Project Title |
Principal Investigator |
Organization |
Total |
|
5K02NS050345-06 |
K02 |
CONNEXIN 32 MUTATIONS IN X-LINKED CMT |
ABRAMS, CHARLES K |
SUNY DOWNSTATE MEDICAL CENTER |
$149,283 |
|
2R01NS046653-06A2 |
R01 |
NA/BICARBONATE COTRANSPORTERS IN BRAIN |
BEVENSEE, MARK OLIVER |
UNIVERSITY OF ALABAMA AT BIRMINGHAM |
$402,646 |
|
5R01NS018400-25 |
R01 |
MOLECULAR PHYSIOLOGY OF BICARBONATE TRANSPORT IN THE BRAIN |
BORON, WALTER F |
CASE WESTERN RESERVE UNIVERSITY |
$463,271 |
|
5R01NS052372-05 |
R01 |
INTERNEURONAL MECHANISMS FOR THE CONTROL OF WALKING |
CHENG, JIANGUO |
CLEVELAND CLINIC LERNER COL/MED-CWRU |
$329,613 |
|
3R01NS034727-13S1 |
R01 |
STRUCTURE OF THE GABA A RECEPTOR BINDING SITES |
CZAJKOWSKI, CYNTHIA M |
UNIVERSITY OF WISCONSIN MADISON |
$359,313 |
|
5R01NS059854-02 |
R01 |
STRUCTURAL REARRANGEMENTS IN GABA-A RECEPTORS |
CZAJKOWSKI, CYNTHIA M |
UNIVERSITY OF WISCONSIN MADISON |
$318,174 |
|
5R01NS036267-11 |
R01 |
MOLECULAR MECHANISMS OF NEURONAL MIGRATIONS |
DEREWENDA, ZYGMUNT S |
UNIVERSITY OF VIRGINIA CHARLOTTESVILLE |
$331,406 |
|
3R01NS036267-11S1 |
R01 |
MOLECULAR MECHANISMS OF NEURONAL MIGRATIONS |
DEREWENDA, ZYGMUNT S |
UNIVERSITY OF VIRGINIA CHARLOTTESVILLE |
$48,729 |
|
5R37NS034407-15 |
R37 |
PROBING RECEPTOR STRUCTURES WITH UNNATURAL AMINO ACIDS |
DOUGHERTY, DENNIS A |
CALIFORNIA INSTITUTE OF TECHNOLOGY |
$414,564 |
|
3R37NS034407-15S1 |
R37 |
PROBING RECEPTOR STRUCTURES WITH UNNATURAL AMINO ACIDS |
DOUGHERTY, DENNIS A |
CALIFORNIA INSTITUTE OF TECHNOLOGY |
$93,632 |
|
1R21NS063053-01A1 |
R21 |
MONAKA -MODULATOR OF NORMAL AND NEUROPATHOLOGICAL SYNAPTIC TRANSMISSION |
FERGUSON, TANYA S. |
UNIVERSITY OF PENNSYLVANIA |
$220,041 |
|
5R01NS058505-03 |
R01 |
A NEW FAMILY OF VOLTAGE-GATED POTASSIUM CHANNEL REGULAORY SUBUNITS |
GOLDSTEIN, STEVE A N |
UNIVERSITY OF CHICAGO |
$460,517 |
|
5F31NS059562-02 |
F31 |
ROLE OF LRP6 IN THE REGULATION OF WNT SIGNALING DURING BRAIN DEVELOPMENT |
GRAY, JASON D |
WEILL MEDICAL COLLEGE OF CORNELL UNIV |
$41,170 |
|
1ZIANS003019-03 |
ZIA |
RNA EDITING OF TRANSPORTERS AND PUMPS |
HOLMGREN, MIGUEL |
|
$262,571 |
|
5R01NS064671-02 |
R01 |
CRCNS: ACTIVITY-DEPENDENT GROWTH CONE GUIDANCE |
HONG, KYONSOO |
NEW YORK UNIVERSITY SCHOOL OF MEDICINE |
$366,524 |
|
5K08NS052454-05 |
K08 |
GABA-A RECEPTOR FUNCTION IN PEDIATRIC FOCAL CORTICAL DYSPLASIA |
JANSEN, LAURA A |
SEATTLE CHILDREN'S HOSPITAL |
$168,291 |
|
2R01NS023684-26A2 |
R01 |
NEURAL SUBSTRATES FOR MATCHING HEARING TO UTTERANCE |
KELLEY, DARCY B |
COLUMBIA UNIV NEW YORK MORNINGSIDE |
$352,188 |
|
5R01NS045937-07 |
R01 |
ROLE OF TH1 SPECIFIC CELL SURFACE MOLECULE TIM-3 IN EAE. |
KUCHROO, VIJAY K |
BRIGHAM AND WOMEN'S HOSPITAL |
$382,813 |
|
1F31NS069510-01 |
F31 |
MOLECULAR REGULATION OF EXPERIENCE-DEPENDENT SYNAPSE AND DENDRITE STABILIZATION |
LESLIE, JENNIFER HELEN |
MASSACHUSETTS INSTITUTE OF TECHNOLOGY |
$41,176 |
|
5R01NS011756-33 |
R01 |
CHEMICAL SYNAPSES - BIOPHYSICAL STUDIES |
LESTER, HENRY A. |
CALIFORNIA INSTITUTE OF TECHNOLOGY |
$340,872 |
|
3R01NS011756-33S1 |
R01 |
CHEMICAL SYNAPSES - BIOPHYSICAL STUDIES |
LESTER, HENRY A. |
CALIFORNIA INSTITUTE OF TECHNOLOGY |
$16,181 |
|
5R01NS029967-17 |
R01 |
NEURAL CALCIUM CHANNELS-REGULATION AND FUNCTION |
LIPSCOMBE, DIANE |
BROWN UNIVERSITY |
$292,226 |
|
3R01NS029967-17S1 |
R01 |
NEURAL CALCIUM CHANNELS-REGULATION AND FUNCTION |
LIPSCOMBE, DIANE |
BROWN UNIVERSITY |
$16,281 |
|
5F32NS063512-02 |
F32 |
ROLE OF MSPS AND TACC DURING AXON GUIDANCE |
LOWERY, LAURA A |
HARVARD UNIVERSITY (MEDICAL SCHOOL) |
$48,860 |
|
3R01NS035812-12S1 |
R01 |
ANALYSIS OF GLUTAMATE RECEPTOR FUNCTION IN C. ELEGANS |
MARICQ, ANDRES VILLU |
UNIVERSITY OF UTAH |
$90,000 |
|
5R01NS057674-02 |
R01 |
VITAMIN C TRANSPORTERS IN THE BRAIN |
MAY, JAMES M |
VANDERBILT UNIVERSITY |
$302,203 |
|
5R01NS056415-02 |
R01 |
NEUROMUSCULAR JUNCTION FORMATION |
MEI, LIN |
MEDICAL COLLEGE OF GEORGIA (MCG) |
$294,000 |
|
3R01NS056415-02S1 |
R01 |
NEUROMUSCULAR JUNCTION FORMATION |
MEI, LIN |
MEDICAL COLLEGE OF GEORGIA (MCG) |
$224,522 |
|
1ZIANS003000-07 |
ZIA |
CONFORMATIONAL CHANGES IN CIC CHLORIDE TRANSPORTERS |
MINDELL, JOSEPH A |
|
$62,410 |
|
5K01NS052551-03 |
K01 |
UNDERSTANDING DIRECTED RETINAL CELL AXON GUIDANCE. |
MORRIS, ANDREA R |
HAVERFORD COLLEGE |
$117,218 |
|
7R01NS049417-04 |
R01 |
THE NIPA 1 PROTEIN IN SPASTIC PARAPLEGIA AND DEVELOPMENT |
NICHOLLS, ROBERT D |
UNIVERSITY OF PITTSBURGH AT PITTSBURGH |
$278,677 |
|
5R01NS062156-02 |
R01 |
COMBINED COMPUTATIONAL AND WET LAB SCREENING FOR DRUGS TESTED VIA OATS |
NIGAM, SANJAY K |
UNIVERSITY OF CALIFORNIA SAN DIEGO |
$337,969 |
|
1R21NS058330-01A2 |
R21 |
NOVEL ANALGESICS FROM AUSTRALIAN FUNNEL-WEB SPIDER VENOM |
NITABACH, MICHAEL NATHAN |
YALE UNIVERSITY |
$248,250 |
|
5P01NS035985-10 |
P01 |
MOLECULAR DETERMINANTS OF EXTRASYNAPTIC GABA RECEPTOR FUNCTION ON CEREBELLAR GRAN |
OTIS, THOMAS S |
UNIVERSITY OF CALIFORNIA LOS ANGELES |
$238,894 |
|
5R01NS038296-09 |
R01 |
APOPTOSIS AND RENEWAL OF NEURAL PROGENITOR CELLS |
RAKIC, PASKO |
YALE UNIVERSITY |
$313,357 |
|
1R15NS067566-01 |
R15 |
NEUROTRANSMITTER FATE SPECIFICATION AND THE ROLE OF VOLTAGE-GATED CALCIUM CHANNEL |
SAHA, MARGARET S |
COLLEGE OF WILLIAM AND MARY |
$213,017 |
|
5R01NS040972-09 |
R01 |
DEVELOPMEBNT OF THE VERTEBRATE NERVOUS SYSTEM |
SOKOL, SERGEI Y |
MOUNT SINAI SCHOOL OF MEDICINE OF NYU |
$412,472 |
|
1R01NS057690-01A2 |
R01 |
GENETIC SCREENS FOR ANALYSIS OF CA-DEPENDENT TRANSMITTER SPECIFICATION |
SPITZER, NICHOLAS C |
UNIVERSITY OF CALIFORNIA SAN DIEGO |
$280,389 |
|
1R21NS064417-01 |
R21 |
PHARMACOLOGY OF CONNEXIN CHANNELS: STRUCTURE-ACTIVITY STUDIES. |
SRINIVAS, MIDUTURU |
STATE COLLEGE OF OPTOMETRY |
$219,927 |
|
1F31NS063668-01A1 |
F31 |
ROLE OF CPEB IN DENDRITIC CAMKLLA MRNA TRANSPORT AND TRANSLATION |
SWANGER, SHARON ANN |
EMORY UNIVERSITY |
$28,866 |
|
1RC1NS068966-01 |
RC1 |
GENOME WIDE SCREENING OF TRANSMEMBRANE ACCESSORY SUBUNITS OF ION CHANNELS |
TOMITA, SUSUMU |
YALE UNIVERSITY |
$500,000 |
|
5R21NS062204-02 |
R21 |
IDENTIFICATION OF LIGANDS THAT BIND TO THE ORPHAN DELTA2 RECEPTOR |
TRAYNELIS, STEPHEN F. |
EMORY UNIVERSITY |
$169,531 |
|
5R01NS035909-13 |
R01 |
GENES ESSENTIAL TO MOTOR AXON GUIDANCE IN DROSOPHILA |
VAN VACTOR, DAVID L |
HARVARD UNIVERSITY (MEDICAL SCHOOL) |
$371,658 |
|
1R01NS063878-01A2 |
R01 |
MACROPHAGES, NR2B-CONTAINING NMDA RECEPTORS AND HIV DEMENTIA |
XIONG, HUANGUI HANK |
UNIVERSITY OF NEBRASKA MEDICAL CENTER |
$371,250 |
|
5R01NS048834-05 |
R01 |
ANDROGEN MODULATION OF VOCAL NEURONS |
YAMAGUCHI, AYAKO |
BOSTON UNIVERSITY |
$283,294 |
|
5F31NS057872-03 |
F31 |
THE ROLE CELLULAR METABOLISM IN REGULATING APOPTOSIS |
YI, CAROLINE H |
HARVARD UNIVERSITY (MEDICAL SCHOOL) |
$28,264 |
|
|
|
|
|
Total |
$11,306,510 |