Project

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Transcriptional mechanisms of circuit formation and synapse specification

Applicant Scheiffele Peter
Number 127440
Funding scheme Sinergia
Research institution Abteilung Zellbiologie Biozentrum Universität Basel
Institution of higher education University of Basel - BS
Main discipline Neurophysiology and Brain Research
Start/End 01.01.2010 - 31.12.2013
Approved amount 1'200'000.00
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All Disciplines (4)

Discipline
Neurophysiology and Brain Research
Cellular Biology, Cytology
Genetics
Embryology, Developmental Biology

Keywords (6)

synaptic specificity; synaptic transmission; brain function; cerebellum; genetic model; mouse

Lay Summary (English)

Lead
Lay summary
The ability of the nervous system to integrate complex sensory information and produce well-controlled behaviors relies on the precise assembly of neuronal networks during development. The goal of this collaborative project is to examine two key aspects of circuit assembly:The first aspect is the topographic organization of neuronal projections that connect specific parts of one brain area with a second area. This property of neuronal circuits ensures that positional information of sensory inputs is maintained and can be integrated. We will focus specifically on two major afferent systems in the mouse brainstem and their unique synapses: Calyx of Held synapses formed by globular bushy cells in the medial nucleus of the trapezoid body (MNTB) and cerebellar mossy fiber synapses formed by pontine afferents in the cerebellum.The second aspect is the elaboration of specialized synaptic structures. Synapses are the key processing units that tie individual neurons into networks. The functional properties of individual synapses have important impact on the transduction of neuronal information, e.g. synaptic properties determine whether signals are amplified with repetitive stimulation, whether small stimuli elicit responses in a synaptic partner or, alternatively, whether only strong accumulating stimulation leads to activation of the synaptic partner cell.The key hypothesis addressed in this proposal is that transcriptional programs in neuronal cells provide a code for the topography and specificity of synaptic partner choice and for the differentiation of specialized presynaptic structures. We will examine the role of transcription factors in specifying spatially restricted neuronal populations with specific projection patterns, the role of target-derived signals that drive the elaboration of the structurally and functionally highly specialized presynaptic structures.The collaborative approach will allow us to integrate data from the two model systems (cerebellar mossy fiber synapses and calyx of Held synapses) to define conceptual similarities but also to provide insights into context-specific (divergent) roles of molecular mechanisms for neuronal wiring. The three investigators participating in this project each provide unique and specialized forms of expertise that are required for jointly achieving the goals of this project. This expertise includes: (1) insight into the anatomical fine structure of the brainstem, (2) advanced mouse genetic techniques, (3) expertise in electrophysiological studies on synaptic function, (4) cell biological approaches to obtain a mechanistical understanding of synaptic specificity.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Assembly of the Auditory Circuitry by a Hox Genetic Network in the Mouse Brainstem
Di Bonito Maria, Narita Yuichi, Avallone Bice, Sequino Luigi, Mancuso Marta, Andolfi Gennaro, Franze Anna Maria, Puelles Luis, Rijli Filippo M., Studer Michele (2013), Assembly of the Auditory Circuitry by a Hox Genetic Network in the Mouse Brainstem, in PLOS GENETICS, 9(2), e1003249.
BMP signaling specifies the development of a large and fast CNS synapse
Xiao Le, Michalski Nicolas, Kronander Elin, Gjoni Enida, Genoud Christel, Knott Graham, Schneggenburger Ralf (2013), BMP signaling specifies the development of a large and fast CNS synapse, in NATURE NEUROSCIENCE, 16(7), 856-856.
Evolutionary divergence of trigeminal nerve somatotopy in amniotes
Rhinn Muriel, Miyoshi Kanako, Watanabe Aki, Kawaguchi Masahumi, Ito Fumihiro, Kuratani Shigeru, Baker Clare V. H., Murakami Yasunori, Rijli Filippo M. (2013), Evolutionary divergence of trigeminal nerve somatotopy in amniotes, in JOURNAL OF COMPARATIVE NEUROLOGY, 521(6), 1378-1394.
Ezh2 Orchestrates Topographic Migration and Connectivity of Mouse Precerebellar Neurons
Di Meglio Thomas, Kratochwil Claudius F., Vilain Nathalie, Loche Alberto, Vitobello Antonio, Yonehara Keisuke, Hrycaj Steven M., Roska Botond, Peters Antoine H. F. M., Eichmann Anne, Wellik Deneen, Ducret Sebastien, Rijli Filippo M. (2013), Ezh2 Orchestrates Topographic Migration and Connectivity of Mouse Precerebellar Neurons, in SCIENCE, 339(6116), 204-207.
Mouse Hoxa2 mutations provide a model for microtia and auricle duplication
Minoux Maryline, Kratochwil Claudius F., Ducret Sebastien, Amin Shilu, Kitazawa Taro, Kurihara Hiroki, Bobola Nicoletta, Vilain Nathalie, Rijli Filippo M. (2013), Mouse Hoxa2 mutations provide a model for microtia and auricle duplication, in DEVELOPMENT, 140(21), 4386-4397.
mSYD1A, a Mammalian Synapse-Defective-1 Protein, Regulates Synaptogenic Signaling and Vesicle Docking
Wentzel Corinna, Sommer Julia E., Nair Ramya, Stiefvater Adeline, Sibarita Jean-Baptiste, Scheiffele Peter (2013), mSYD1A, a Mammalian Synapse-Defective-1 Protein, Regulates Synaptogenic Signaling and Vesicle Docking, in NEURON, 78(6), 1012-1023.
Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling
Budreck Elaine C., Kwon Oh-Bin, Jung Jung Hoon, Baudouin Stephane, Thommen Albert, Kim Hye-Sun, Fukazawa Yugo, Harada Harumi, Tabuchi Katsuhiko, Shigemoto Ryuichi, Scheiffele Peter, Kim Joung-Hun (2013), Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 110(2), 725-730.
NEUROSCIENCE Sculpting neuronal connectivity
Sylwestrak Emily, Scheiffele Peter (2013), NEUROSCIENCE Sculpting neuronal connectivity, in NATURE, 503(7474), 42-43.
Preparing for Your Future as You Grow
Scheiffele Peter (2013), Preparing for Your Future as You Grow, in NEURON, 78(5), 751-752.
Robo3-driven axon midline crossing conditions functional maturation of a large commissural synapse.
Michalski Nicolas, Babai Norbert, Renier Nicolas, Perkel David J, Chédotal Alain, Schneggenburger Ralf (2013), Robo3-driven axon midline crossing conditions functional maturation of a large commissural synapse., in Neuron, 78(5), 855-68.
The cre/lox system to assess the development of the mouse brain
Kratochwil Claudius F., Rijli Filippo M. (2013), The cre/lox system to assess the development of the mouse brain, Springer (Humana Press), New York 1082.
Total Synthesis of Gelsemiol
Burch Patrick, Binaghi Massimo, Scherer Manuel, Wentzel Corinna, Bossert David, Eberhardt Luc, Neuburger Markus, Scheiffele Peter, Gademann Karl (2013), Total Synthesis of Gelsemiol, in CHEMISTRY-A EUROPEAN JOURNAL, 19(8), 2589-2591.
Transcriptional Regulation of Tangential Neuronal Migration in the Vertebrate Hindbrain
Di Meglio Thomas, Rijli Filippo M. (2013), Transcriptional Regulation of Tangential Neuronal Migration in the Vertebrate Hindbrain, Elsevier, USA, 377-404.
Ca2+ channels and transmitter release at the active zone
Schneggenburger Ralf, Han Yunyun, Kochubey Olexiy (2012), Ca2+ channels and transmitter release at the active zone, in CELL CALCIUM, 52(3-4), 199-207.
Choreographing the Axo-Dendritic Dance
Scheiffele Peter, Iijima Takatoshi (2012), Choreographing the Axo-Dendritic Dance, in DEVELOPMENTAL CELL, 23(5), 923-924.
Growth Cone MKK7 mRNA Targeting Regulates MAP1b-Dependent Microtubule Bundling to Control Neurite Elongation
Feltrin Daniel, Fusco Ludovico, Witte Harald, Moretti Francesca, Martin Katrin, Letzelter Michel, Fluri Erika, Scheiffele Peter, Pertz Olivier (2012), Growth Cone MKK7 mRNA Targeting Regulates MAP1b-Dependent Microtubule Bundling to Control Neurite Elongation, in PLOS BIOLOGY, 10(12), 1-23.
Opposing Roles for Hoxa2 and Hoxb2 in Hindbrain Oligodendrocyte Patterning
Miguez Andres, Ducret Sebastien, Di Meglio Thomas, Parras Carlos, Hmidan Hatem, Haton Celine, Sekizar Sowmya, Mannioui Abdelkrim, Vidal Marie, Kerever Aurelien, Nyabi Omar, Haigh Jody, Zalc Bernard, Rijli Filippo M., Thomas Jean-Leon (2012), Opposing Roles for Hoxa2 and Hoxb2 in Hindbrain Oligodendrocyte Patterning, in JOURNAL OF NEUROSCIENCE, 32(48), 17172-17172.
Shared Synaptic Pathophysiology in Syndromic and Nonsyndromic Rodent Models of Autism
Baudouin Stephane J., Gaudias Julien, Gerharz Stefan, Hatstatt Laetitia, Zhou Kuikui, Punnakkal Pradeep, Tanaka Kenji F., Spooren Will, Hen Rene, De Zeeuw Chris I., Vogt Kaspar, Scheiffele Peter (2012), Shared Synaptic Pathophysiology in Syndromic and Nonsyndromic Rodent Models of Autism, in SCIENCE, 338(6103), 128-132.
Development of Axon-Target Specificity of Ponto-Cerebellar Afferents
Kalinovsky A, Boukhtouche F, Blazeski R, Bornmann C, Suzuki N, Mason CA, Scheiffele P (2011), Development of Axon-Target Specificity of Ponto-Cerebellar Afferents, in PLOS BIOLOGY, 9(2), e1001013-e1001013.
Distinct mechanisms regulate GABA(A) receptor and gephyrin clustering at perisomatic and axo-axonic synapses on CA1 pyramidal cells
Panzanelli Patrizia, Gunn Benjamin G., Schlatter Monika C., Benke Dietmar, Tyagarajan Shiva K., Scheiffele Peter, Belelli Delia, Lambert Jeremy J., Rudolph Uwe, Fritschy Jean-Marc (2011), Distinct mechanisms regulate GABA(A) receptor and gephyrin clustering at perisomatic and axo-axonic synapses on CA1 pyramidal cells, in JOURNAL OF PHYSIOLOGY-LONDON, 589(20), 4959-4980.
Hox and Pbx Factors Control Retinoic Acid Synthesis during Hindbrain Segmentation
Vitobello Antonio, Ferretti Elisabetta, Lampe Xavier, Vilain Nathalie, Ducret Sebastien, Ori Michela, Spetz Jean-Francois, Selleri Licia, Rijli Filippo M. (2011), Hox and Pbx Factors Control Retinoic Acid Synthesis during Hindbrain Segmentation, in DEVELOPMENTAL CELL, 20(4), 469-482.
Regulation of transmitter release by Ca2+ and synaptotagmin: insights from a large CNS synapse
Kochubey Olexiy, Lou Xuelin, Schneggenburger Ralf (2011), Regulation of transmitter release by Ca2+ and synaptotagmin: insights from a large CNS synapse, in TRENDS IN NEUROSCIENCES, 34(5), 237-246.
RIM Determines Ca2+ Channel Density and Vesicle Docking at the Presynaptic Active Zone
Han Yunyun, Kaeser Pascal S., Suedhof Thomas C., Schneggenburger Ralf (2011), RIM Determines Ca2+ Channel Density and Vesicle Docking at the Presynaptic Active Zone, in NEURON, 69(2), 304-316.
SAM68 Regulates Neuronal Activity-Dependent Alternative Splicing of Neurexin-1
Iijima Takatoshi, Wu Karen, Witte Harald, Hanno-Iijima Yoko, Glatter Timo, Richard Stephane, Scheiffele Peter (2011), SAM68 Regulates Neuronal Activity-Dependent Alternative Splicing of Neurexin-1, in CELL, 147(7), 1601-1614.
Synaptotagmin Increases the Dynamic Range of Synapses by Driving Ca2+-Evoked Release and by Clamping a Near-Linear Remaining Ca2+ Sensor
Kochubey Olexiy, Schneggenburger Ralf (2011), Synaptotagmin Increases the Dynamic Range of Synapses by Driving Ca2+-Evoked Release and by Clamping a Near-Linear Remaining Ca2+ Sensor, in NEURON, 69(4), 736-748.
Developmental expression of Synaptotagmin isoforms in single calyx of Held-generating neurons
Xiao Le, Han Yunyun, Runne Heike, Murray Heather, Kochubey Olexiy, Luthi-Carter Ruth, Schneggenburger Ralf (2010), Developmental expression of Synaptotagmin isoforms in single calyx of Held-generating neurons, in MOLECULAR AND CELLULAR NEUROSCIENCE, 44(4), 374-385.
Flexible Accelerated STOP Tetracycline Operator-Knockin (FAST): A Versatile and Efficient New Gene Modulating System
Tanaka Kenji F., Ahmari Susanne E., Leonardo E. David, Richardson-Jones Jesse W., Budreck Elaine C., Scheiffele Peter, Sugio Shouta, Inamura Naoko, Ikenaka Kazuhiro, Hen Rene (2010), Flexible Accelerated STOP Tetracycline Operator-Knockin (FAST): A Versatile and Efficient New Gene Modulating System, in BIOLOGICAL PSYCHIATRY, 67(8), 770-773.
Genetics and Cell Biology of Building Specific Synaptic Connectivity
Shen Kang, Scheiffele Peter (2010), Genetics and Cell Biology of Building Specific Synaptic Connectivity, in ANNUAL REVIEW OF NEUROSCIENCE, VOL 33, 33, 473-507.
Interaction between facilitation and depression at a large CNS synapse reveals mechanisms of short-term plasticity.
Müller Martin, Goutman Juan D, Kochubey Olexiy, Schneggenburger Ralf (2010), Interaction between facilitation and depression at a large CNS synapse reveals mechanisms of short-term plasticity., in The Journal of neuroscience : the official journal of the Society for Neuroscience, 30(6), 2007-16.
NEUROSCIENCE Angelman syndrome connections
Scheiffele Peter, Beg Asim A. (2010), NEUROSCIENCE Angelman syndrome connections, in NATURE, 468(7326), 907-908.
SnapShot: Neuroligin-Neurexin Complexes
Baudouin Stephane, Scheiffele Peter (2010), SnapShot: Neuroligin-Neurexin Complexes, in CELL, 141(5), 908-908.
Munc18-1 is a dynamically regulated PKC target during short-term enhancement of transmitter release
Genç Özgür, Kochubey Olexiy, Toonen Ruud F, Verhage Matthijs, Schneggenburger Ralf, Munc18-1 is a dynamically regulated PKC target during short-term enhancement of transmitter release, in elife, 1.
Transcriptional regulation of tangential neuron migration in the developing vertebrate hindbrain
Di Meglio Thomas, Rijli Filippo, Transcriptional regulation of tangential neuron migration in the developing vertebrate hindbrain, in P. Rakic & J. Rubenstein (ed.), Elsevier, Amsterdam.

Collaboration

Group / person Country
Types of collaboration
Institut de la Vision, Paris France (Europe)
- Publication

Scientific events



Self-organised

Title Date Place
3rd Sinergia Group Meeting 16.01.2012 EPFL, Lausanne, Switzerland
2nd Sinergia Group Meeting 25.01.2011 FMI, Basel, Switzerland
1st Sinergia Group Meeting 28.01.2010 Biozentrum, Basel, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Le mystère de la connexion de nos neurones se dissipe 24 Heures - 27.05.2013 Western Switzerland 2013
Media relations: print media, online media L'EPFL décrypte le fonctionnement d'une synapse géante Le Temps - 26.05.2013 Western Switzerland 2013
Media relations: print media, online media Scientists discover the origin of a giant synapse EPFL press release - 29.05.2013 Western Switzerland International Rhaeto-Romanic Switzerland German-speaking Switzerland Italian-speaking Switzerland 2013
Media relations: print media, online media Wachstum von Riesensynapsen entschlüsselt Tages Anzeiger - 28.05.2013 German-speaking Switzerland 2013

Associated projects

Number Title Start Funding scheme
125209 Molecular Mechanisms of Neuronal Synapse Formation 01.06.2009 Project funding (Div. I-III)
139219 Multi-user two-photon microscope facility for advanced neuron imaging in-vivo and in-vitro 01.07.2012 R'EQUIP
138320 Role of Synaptotagmin isoforms in the Ca2+ - regulation of transmitter release at fast CNS synapses 01.10.2011 Project funding (Div. I-III)
154455 Control of functional and structural plasticity of synapses by bone morphogenetic protein signaling 01.01.2015 Sinergia
149573 Transcriptional and epigenetic regulation of precerebellar neuron migration and connectivity 01.01.2014 Project funding (Div. I-III)
140944 Molecular Mechanisms of Neuronal Synapse Formation 01.08.2012 Project funding (Div. I-III)

Abstract

The ability of the nervous system to integrate complex sensory information and produce well-controlled behaviors relies on the precise assembly of neuronal networks during development. The goal of this collaborative project is to examine two key aspects of circuit assembly during nervous system development: The topographic organization of axonal projections, and the elaboration of specialized presynaptic structures with the appropriate target cells. The key hypothesis addressed in this proposal is that transcriptional programs in neuronal cells provide a code for the specificity of synaptic partner choice and for the differentiation of specialized presynaptic structures. We will examine the role of transcription factors in specifying spatially restricted neuronal populations with specific projection patterns, the role of target-derived signals that drive the elaboration of the structurally and functionally highly specialized presynaptic structures.To accomplish these goals we will focus on two major afferent systems in the mouse brainstem and their unique synapses: Calyx of Held synapses formed by globular bushy cells in the medial nucleus of the trapezoid body (MNTB) and mossy fiber synapses formed by pontine afferents in the cerebellum. Investigating the function of key transcriptional and synaptic signaling components in these two well-characterized neuronal systems will enable us to determine molecular mechanisms of synaptic specificity in each system. More importantly, the collaborative approach will allow us to integrate data from the two model systems to define conceptual similarities but also to provide insights into context-specific (divergent) roles of molecular mechanisms for neuronal wiring.The three investigators participating in this project each provide unique and specialized forms of expertise that are required to jointly achieve the goals of this project. This expertise includes: (1) detailed insight into the anatomical fine structure of brainstem circuits (all investigators), (2) advanced mouse genetic techniques for the conditional labeling and manipulation of cells in the mouse central nervous system (Rijli), (3) expertise in electrophysiological studies on synaptic function (Schneggenburger), (4) cell biological approaches to obtain a mechanistical understanding of synaptic specificity (Scheiffele). These individual strengths are further complemented by extensive sharing of resources and facilities available at the three participating institutions (EPFL Lausanne, Biozentrum Basel, Friedrich Miescher Institut Basel) and by joint organization and sharing of a collection of genetic mouse models that in combination enable a detailed genetic analysis of the selected brainstem circuits in an in vivo model. These synergies will be fostered further by well-developed sharing plans as well as training plans for the research personnel.The complexity of synaptic connectivity established during development can only be addressed using an interdisciplinary approach, which integrates genetics, cell biology, biophysical and anatomical methods. This Sinergia project aims to realize such an approach by joining forces between three investigators with complementary expertise with the goal to unravel the molecular mechanisms of synaptic specificity in the vertebrate brainstem.
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