Project

Back to overview

Molecular Mechanisms of Neuronal Synapse Formation

English title Molecular Mechanisms of Neuronal Synapse Formation
Applicant Scheiffele Peter
Number 140944
Funding scheme Project funding (Div. I-III)
Research institution Abteilung Zellbiologie Biozentrum Universität Basel
Institution of higher education University of Basel - BS
Main discipline Cellular Biology, Cytology
Start/End 01.08.2012 - 31.07.2015
Approved amount 841'062.00
Show all

All Disciplines (2)

Discipline
Cellular Biology, Cytology
Neurophysiology and Brain Research

Keywords (5)

Neural Development; Cell adhesion; Neuronal signaling mechanisms; Synapse Formation; Mouse genetics

Lay Summary (English)

Lead
Lay summary

During the development of the brain, which occurs in the embryo but also after birth, neuronal cells extend protrusions called axons and dendrites. Axons can span long distances from millimeters to meters. Once an axon reaches its destination it will form connections on the dendrites of other cells. These connections are called “synapses” and enable the two cells to communicate with each other. Synapses are assembled with exquisite selectivity. Only specific neuronal partners form synapses with each other and the location and number of synaptic connections is highly reproducible. This is remarkable if one considers that an axon passes hundreds or thousands of potential partners and selectively recognizes the appropriate partners for synapse formation. In our work, we are examining this question and hope to define the cellular interactions and signaling events that control formation of specific synapses.

 

In previous studies, we have discovered that a complex of proteins with adhesive properties, called the neuroligin-neurexin complex, has remarkable synapse-organizing activities. That means neuroligin and neurexin proteins are presented at the opposing surfaces of two neuronal cells and can orchestrate the conversion of these cell contacts into functional synaptic junctions. A central goal of the work described in this proposal is to understand the function of the neuroligin-neurexin adhesion complex in the central nervous system. Notably, neuroligins and neurexins are encoded by gene families that produce multiple different protein isoforms. This means in the case of neurexins there are over 3,000 variants that slightly differ in their protein sequence and their ability to interact with the neuroligin molecules.  To examine the molecular mechanisms underlying the assembly of functional neuronal networks, we are mapping neurexin isoform expression in genetically identified cells and test the mechanisms of synaptic specificity in the cerebellum, a brain structure that controls the coordination of motor and sensory information.

 

Mutations in neuroligin and neurexin genes in humans are associated with autism-spectrum disorders. Therefore, we hope that understanding the basic function of these proteins in the nervous system will also shed some light on the functional abnormalities underlying autistic disorders.

 

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Potent degradation of neuronal miRNAs induced by highly complementary targets.
de la Mata Manuel, Gaidatzis Dimos, Vitanescu Mirela, Stadler Michael B, Wentzel Corinna, Scheiffele Peter, Filipowicz Witold, Großhans Helge (2015), Potent degradation of neuronal miRNAs induced by highly complementary targets., in EMBO reports, 16(4), 500-11.
Quantitative isoform-profiling of highly diversified recognition molecules.
Schreiner Dietmar, Simicevic Jovan, Ahrné Erik, Schmidt Alexander, Scheiffele Peter (2015), Quantitative isoform-profiling of highly diversified recognition molecules., in eLife, 4, 07794-07794.
Alternative splicing coupled nonsense-mediated decay generates neuronal cell type-specific expression of SLM proteins.
Traunmüller Lisa, Bornmann Caroline, Scheiffele Peter (2014), Alternative splicing coupled nonsense-mediated decay generates neuronal cell type-specific expression of SLM proteins., in The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(50), 16755-61.
Neuronal cell type-specific alternative splicing is regulated by the KH domain protein SLM1.
Iijima Takatoshi, Iijima Yoko, Witte Harald, Scheiffele Peter (2014), Neuronal cell type-specific alternative splicing is regulated by the KH domain protein SLM1., in The Journal of cell biology, 204(3), 331-42.
Polymorphic receptors: neuronal functions and molecular mechanisms of diversification.
Schreiner Dietmar, Nguyen Thi-Minh, Scheiffele Peter (2014), Polymorphic receptors: neuronal functions and molecular mechanisms of diversification., in Current opinion in neurobiology, 27, 25-30.
Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins.
Schreiner Dietmar, Nguyen Thi-Minh, Russo Giancarlo, Heber Steffen, Patrignani Andrea, Ahrné Erik, Scheiffele Peter (2014), Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins., in Neuron, 84(2), 386-98.
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), 1012-23.
Neuroscience: Sculpting neuronal connectivity.
Sylwestrak Emily, Scheiffele Peter (2013), Neuroscience: Sculpting neuronal connectivity., in Nature, 503(7474), 42-3.
Preparing for your future as you grow.
Scheiffele Peter (2013), Preparing for your future as you grow., in Neuron, 78(5), 751-2.
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 (Weinheim an der Bergstrasse, Germany), 19(8), 2589-91.

Awards

Title Year
Robert Bing Prize of the Swiss Academy of Medical Sciences 2014

Associated projects

Number Title Start Funding scheme
127440 Transcriptional mechanisms of circuit formation and synapse specification 01.01.2010 Sinergia
157700 Lightsheet microscopy 01.12.2014 R'EQUIP
125209 Molecular Mechanisms of Neuronal Synapse Formation 01.06.2009 Project funding (Div. I-III)
125759 NCCR SYNAPSY: The synaptic bases of mental diseases (phase I) 01.10.2010 National Centres of Competence in Research (NCCRs)
158905 RNA-based mechanisms of neuronal plasticity 01.01.2015 International short research visits
160319 Molecular mechanisms of neuronal synapse formation 01.08.2015 Project funding (Div. I-III)
179432 Molecular mechanisms of neuronal synapse formation 01.08.2018 Project funding (Div. I-III)

Abstract

The assembly of functional neuronal circuits during development of the central nervous system requires an array of selective cell-cell interactions. These interactions direct cell migration, targeted growth and branching of axonal and dendritic processes, recognition of appropriate target cells, differentiation of pre- and postsynaptic structures, and recruitment of synapse-specific release machinery and neurotransmitter receptors. The aim of our studies is to understand the molecular mechanisms underlying the formation of specific connections between neurons in the central nervous system. In particular, we are examining the trans-synaptic signals that coordinate the choice of synaptic partners, assembly of synaptic junctions and stabilization of appropriate contacts. To address these questions, we are using a combination of functional in vitro assays that facilitate the identification of new signaling mechanisms and in vivo analysis of neuronal circuits in the mouse cerebellum. The cerebellum is an excellent model system for the analysis of synaptic specificity due to it’s highly organized structure. Moreover, we have established genetic labeling and marking techniques that facilitate dissection of synaptic specificity in vivo system.Over the past years, we characterized the function of a family of neuronal cell adhesion molecules, called neuroligins and neurexins that form a heterophilic cell adhesion complex and that have potent synapse-organizing activities. These activities are regulated through extensive alternative splicing in sequences encoding the extracellular domains of these proteins. In our ongoing projects we are applying cell biological, biochemical, genetic and anatomical approaches to explore the molecular mechanisms underlying the choice of specific isoforms and isoform-specific functions. In the long-term, we aim to test the hypothesis that alternative splicing of neuroligin and neurexin isoforms underlies cell type- and synapse-specific interactions or properties in neuronal circuits. In a second set of studies we will examine how trans-synaptic cell surface interactions may be interpreted to guide the assembly of presynaptic structures. In particular, we are focusing on a novel protein called Synapse-defective-1 which has emerged as a key regulator of presynaptic assembly in invertebrates. The following aims will be the main focus of the research in my laboratory for the coming years and are described in detail in the Research Plan.(1) Signaling Mechanisms Downstream of Synaptic Adhesion Molecules: In the vertebrate CNS multiple trans-synaptic adhesion systems have been identified that organize presynaptic terminals. However, it is unknown how adhesion complexes reorganize the axonal cytoskeleton and drive recruitment of active zone components and synaptic vesicles. We will examine the function of mammalian orthologues of Synapse-defective 1 (SYD1), a key regulator of synapse formation in invertebrates.(2) Testing the Neurexin Code in Neuronal Networks: With over 3,000 isoforms, the Neurexins represent one of the molecularly most diverse families of neuronal cell surface proteins in vertebrates. Our previous studies suggest that neurexin splice isoform diversity underlies a synapse-specific adhesive code. In this project we will combine single cell analysis of genetically identified cerebellar neurons and cell type specific ablation of specific neurexin splice variants to examine the contribution of neurexins to neuronal identity and the selective wiring of cerebellar circuits.(3) Activity-dependent Alternative Splicing Regulation of Synaptic Receptors: In this project we are analyzing the molecular machinery that regulates neurexin splice isoform choice. We have identified an alternative splicing factor that associates with neurexin-1 mRNA and is essential for the regulation of neurexin alternative splicing in vivo. Specifically, this splicing factor regulates the selection of exon 20, an alternative exon that plays a fundamental role in synapse-specific trans-synaptic signaling through select ligand interactions.
-