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Subcellular sorting of neuregulins controls the assembly of excitatory-inhibitory cortical circuits.

David Exposito-Alonso | Catarina Osório | Clémence Bernard | Sandra Pascual-García | Isabel Del Pino | Oscar Marín | Beatriz Rico
eLife | 2020

The assembly of specific neuronal circuits relies on the expression of complementary molecular programs in presynaptic and postsynaptic neurons. In the cerebral cortex, the tyrosine kinase receptor ErbB4 is critical for the wiring of specific populations of GABAergic interneurons, in which it paradoxically regulates both the formation of inhibitory synapses as well as the development of excitatory synapses received by these cells. Here, we found that Nrg1 and Nrg3, two members of the neuregulin family of trophic factors, regulate the inhibitory outputs and excitatory inputs of interneurons in the mouse cerebral cortex, respectively. The differential role of Nrg1 and Nrg3 in this process is not due to their receptor-binding EGF-like domain, but rather to their distinctive subcellular localization within pyramidal cells. Our study reveals a novel strategy for the assembly of cortical circuits that involves the differential subcellular sorting of family-related synaptic proteins.

Pubmed ID: 33320083

Antibodies used in this publication

Associated grants

  • Agency: Medical Research Council, United Kingdom
    Id: MR/N026063/1
  • Agency: Medical Research Council, United Kingdom
    Id: MR/S010785/1
  • Agency: Innovative Medicines Initiative, International
    Id: AIMS-2-TRIALS,777394

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This is a list of tools and resources that we have found mentioned in this publication.


NeuroMab (tool)

RRID:SCR_003086

A national mouse monoclonal antibody generating resource for biochemical and immunohistochemical applications in mammalian brain. NeuroMabs are generated from mice immunized with synthetic and recombinant immunogens corresponding to components of the neuronal proteome as predicted from genomic and other large-scale cloning efforts. Comprehensive biochemical and immunohistochemical analyses of human, primate and non-primate mammalian brain are incorporated into the initial NeuroMab screening procedure. This yields a subset of mouse mAbs that are optimized for use in brain (i.e. NeuroMabs): for immunocytochemical-based imaging studies of protein localization in adult, developing and pathological brain samples, for biochemical analyses of subunit composition and post-translational modifications of native brain proteins, and for proteomic analyses of native brain protein networks. The NeuroMab facility was initially funded with a five-year U24 cooperative grant from NINDS and NIMH. The initial goal of the facility for this funding period is to generate a library of novel NeuroMabs against neuronal proteins, initially focusing on membrane proteins (receptors/channels/transporters), synaptic proteins, other neuronal signaling molecules, and proteins with established links to disease states. The scope of the facility was expanded with supplements from the NIH Blueprint for Neuroscience Research to include neurodevelopmental targets, the NIH Roadmap for Medical Research to include epigenetics targets, and NIH Office of Rare Diseases Research to include rare disease targets. These NeuroMabs will then be produced on a large scale and made available to the neuroscience research community on an inexpensive basis as tissue culture supernatants or purified immunoglobulin by Antibodies Inc. The UC Davis/NIH NeuroMab Facility makes NeuroMabs available directly to end users and is unable to accommodate sales to distributors for third party distribution. Note, NeuroMab antibodies are now offered through antibodiesinc.

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Clontech (tool)

RRID:SCR_004423

An Antibody supplier

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Cell Signaling Technology (tool)

RRID:SCR_004431

Privately held company that develops and produces antibodies, ELISA kits, ChIP kits, proteomic kits, and other related reagents used to study cell signaling pathways that impact human health.

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NCBI BLAST (tool)

RRID:SCR_004870

Web search tool to find regions of similarity between biological sequences. Program compares nucleotide or protein sequences to sequence databases and calculates statistical significance. Used for identifying homologous sequences.

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Thermo Fisher Scientific (tool)

RRID:SCR_008452

Commercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.

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Jackson ImmunoResearch (tool)

RRID:SCR_010488

A commercial antibody vendor, specializing in secondary antibodies.

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Molecular Probes (tool)

RRID:SCR_013318

An Antibody supplier and subset of ThermoFisher Scientific which provides fluorescence reagents for various experiments and methods.

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Synaptic Systems (tool)

RRID:SCR_013612

An Antibody supplier

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Anti-PSD-95 Antibody (antibody)

RRID:AB_2292909

This monoclonal targets PSD 95

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Anti-Parvalbumin (antibody)

RRID:AB_2619887

This polyclonal targets Parvalbumin

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CB1 (antibody)

RRID:AB_2571592

This polyclonal targets CB1, C-terminal 31 aa (NM007726)

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Phospho-I B (Ser32) (14D4) Rabbit mAb (antibody)

RRID:AB_561111

This monoclonal targets Phospho-I B (Ser32)

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NRG1 type III antibody (antibody)

RRID:AB_2154667

This polyclonal targets Nrg1

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Biotin anti-mouse IgG1 (antibody)

RRID:AB_315062

This monoclonal targets IgG1

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Anti-Gephyrin (antibody)

RRID:AB_887717

This monoclonal targets Gephyrin

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HA-Tag (C29F4) Rabbit mAb (antibody)

RRID:AB_1549585

This monoclonal targets HA-Tag

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Rabbit anti-Parvalbumin (antibody)

RRID:AB_2631173

This unknown targets Parvalbumin

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Anti-GAD67 (antibody)

RRID:AB_2278725

This monoclonal targets GAD67

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R Project for Statistical Computing (software resource)

RRID:SCR_001905

Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.

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Fiji (software resource)

RRID:SCR_002285

Software package as distribution of ImageJ and ImageJ2 together with Java, Java3D and plugins organized into coherent menu structure. Used to assist research in life sciences.

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Leica Application Suite X (resource)

RRID:SCR_013673

Software for image capture, processing and analysis with Leica fluorescence and confocal microscopes.

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B6;129S6-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J (organism)

RRID:IMSR_JAX:007905

Mus musculus with name B6;129S6-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J from IMSR.

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RStudio (software resource)

RRID:SCR_000432

Open source and enterprise ready professional software for R statistical computing environment. Integrated development environment for R. Includes console, syntax highlighting editor that supports direct code execution, as well as tools for plotting, history, debugging and workspace management. Available in open source and commercial editions and runs on desktop Windows, Mac, and Linux or in browser connected to RStudio Server or RStudio Server Pro (Debian/Ubuntu, RedHat/CentOS, and SUSE Linux).

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Bioconductor (software resource)

RRID:SCR_006442

Software repository for R packages related to analysis and comprehension of high throughput genomic data. Uses separate set of commands for installation of packages. Software project based on R programming language that provides tools for analysis and comprehension of high throughput genomic data.

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MATLAB (software resource)

RRID:SCR_001622

Multi paradigm numerical computing environment and fourth generation programming language developed by MathWorks. Allows matrix manipulations, plotting of functions and data, implementation of algorithms, creation of user interfaces, and interfacing with programs written in other languages, including C, C++, Java, Fortran and Python. Used to explore and visualize ideas and collaborate across disciplines including signal and image processing, communications, control systems, and computational finance.

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C57BL/6J (organism)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

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Crl:CD1(ICR) (organism)

RRID:IMSR_CRL:022

Mus musculus with name Crl:CD1(ICR) from IMSR.

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