Expression of mutant Ets protein at the neuromuscular synapse causes alterations in morphology and gene expression.

The localized transcription of several muscle genes at the motor endplate is controlled by the Ets transcription factor GABP. To evaluate directly its contribution to the formation of the neuromuscular junction, we generated transgenic mice expressing a general Ets dominant-negative mutant specifically in skeletal muscle. Quantitative RT-PCR analysis demonstrated that the expression of genes containing an Ets-binding site was severely affected in the mutant mice. Conversely, the expression of other synaptic genes, including MuSK and Rapsyn, was unchanged. In these animals, muscles expressing the mutant transcription factor developed normally, but examination of the post-synaptic morphology revealed marked alterations of both the primary gutters and secondary folds of the neuromuscular junction. Our results demonstrate that Ets transcription factors are crucial for the normal formation of the neuromuscular junction. They further show that Ets-independent mechanisms control the synaptic expression of a distinct set of synaptic genes.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

A Novel Mechanism of P-type ATPase Autoinhibition Involving Both Termini of the Protein

The activity of many P-type ATPases is found to be regulated by interacting proteins or autoinhibitory elements located in N- or C-terminal extensions. An extended C terminus of fungal and plant P-type plasma membrane H+-ATPases has long been recognized to be part of a regulatory apparatus involving an autoinhibitory domain. Here we demonstrate that both the N and the C termini of the plant plasma membrane H+-ATPase are directly involved in controlling the pump activity state and that N-terminal displacements are coupled to secondary modifications taking place at the C-terminal end. This identifies the first group of P-type ATPases for which both ends of the polypeptide chain constitute regulatory domains, which together contribute to the autoinhibitory apparatus. This suggests an intricate mechanism of cis-regulation with both termini of the protein communicating to obtain the necessary control of the enzyme activity state

The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10.

Prolactin-releasing peptide (PrRP) and its receptor G protein-coupled receptor 10 (GPR10) are expressed in brain areas involved in the processing of nociceptive signals. We investigated the role of this new neuropeptidergic system in GPR10-knockout mice. These mice had higher nociceptive thresholds and stronger stress-induced analgesia than wild-type mice, differences that were suppressed by naloxone treatment. In addition, potentiation of morphine-induced antinociception and reduction of morphine tolerance were observed in mutants. Intracerebroventricular administration of PrRP in wild-type mice promoted hyperalgesia and reversed morphine-induced antinociception. PrRP administration had no effect on GPR10-mutant mice, showing that its effects are mediated by GPR10. Anti-opioid effects of neuropeptide FF were found to require a functional PrRP-GPR10 system. Finally, GPR10 deficiency enhanced the acquisition of morphine-induced conditioned place preference and decreased the severity of naloxone-precipitated morphine withdrawal syndrome. Altogether, our data identify the PrRP-GPR10 system as a new and potent negative modulator of the opioid system.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

The coming decade of digital brain research - A vision for neuroscience at the intersection of technology and computing

<p>Brain research has in recent years indisputably entered a new epoch, driven by substantial methodological advances and digitally enabled data integration and modeling at multiple scales – from molecules to the whole system. Major advances are emerging at the intersection of neuroscience with technology and computing. This new science of the brain integrates high-quality basic research, systematic data integration across multiple scales, a new culture of large-scale collaboration and translation into applications. A systematic approach, as pioneered in Europe's Human Brain Project (HBP), will be essential in meeting the pressing medical and technological challenges of the coming decade. The aims of this paper are</p><ul><li>To develop a concept for the coming decade of digital brain research</li><li>To discuss it with the research community at large, with the aim of identifying points of convergence and common goals</li><li>To provide a scientific framework for current and future development of EBRAINS</li><li>To inform and engage stakeholders, funding organizations and research institutions regarding future digital brain research</li><li>To identify and address key ethical and societal issues</li></ul><p>While we do not claim that there is a 'one size fits all' approach to addressing these aspects, we are convinced that discussions around the theme of digital brain research will help drive progress in the broader field of neuroscience.</p><p><strong>As the final version 5 has now been published, comments on this manuscript are now closed. We thank everyone who made a valuable contribution to this paper.</strong></p><p>This manuscript has been developed in a participatory process. The work has been initiated by the Science and Infrastructure Board of the Human Brain Project (HBP), and the entire research community was invited to contribute to shaping the vision by submitting comments. </p><p>All submitted comments were considered and discussed. The final decision on whether edits or additions was made to each version of the manuscript based on an individual comment was made by the Science and Infrastructure Board (SIB) of the Human Brain Project (HBP).</p><p><strong>Supporters of the paper</strong>: Pietro Avanzini, Marc Beyer, Maria Del Vecchio, Jitka Annen, Maurizio Mattia, Steven Laureys, Rosanne Edelenbosch, Rafael Yuste, Jean-Pierre Changeux, Linda Richards, Hye Weon Jessica Kim, Chrysoula Samara, Luis Miguel González de la Garza, Nikoleta Petalidou, Vasudha Kulkarni, Cesar David Rincon, Isabella O'Shea, Munira Tamim Electricwala, Bernd Carsten Stahl, Bahar Hazal Yalcinkaya, Meysam Hashemi, Carola Sales Carbonell, Marcel Carrère, Anthony Randal McIntosh, Hiba Sheheitli, Abolfazl Ziaeemehr, Martin Breyton, Giovanna Ramos Queda, Anirudh NIhalani Vattikonda, Gyorgy Buzsaki, George Ogoh, William Knight, Torbjørn V Ness, Michiel van der Vlag, Marcello Massimini, Thomas Nowontny, Alex Upton, Yaseen Jakhura, Ahmet Nihat Simsek, Michael Hopkins, Addolorata Marasco, Shamim Patel, Jakub Fil, Diego Molinari, Susana Bueno, Lia Domide, Cosimo Lupo, Mu-ming Poo, George Paxinos, Huifang Wang.</p&gt