TY - JOUR A1 - Salehi, Saeede A1 - Zare, Abdolhossein A1 - Prezza, Gianluca A1 - Bader, Jakob A1 - Schneider, Cornelius A1 - Fischer, Utz A1 - Meissner, Felix A1 - Mann, Matthias A1 - Briese, Michael A1 - Sendtner, Michael T1 - Cytosolic Ptbp2 modulates axon growth in motoneurons through axonal localization and translation of Hnrnpr JF - Nature Communications N2 - The neuronal RNA-binding protein Ptbp2 regulates neuronal differentiation by modulating alternative splicing programs in the nucleus. Such programs contribute to axonogenesis by adjusting the levels of protein isoforms involved in axon growth and branching. While its functions in alternative splicing have been described in detail, cytosolic roles of Ptbp2 for axon growth have remained elusive. Here, we show that Ptbp2 is located in the cytosol including axons and growth cones of motoneurons, and that depletion of cytosolic Ptbp2 affects axon growth. We identify Ptbp2 as a major interactor of the 3’ UTR of Hnrnpr mRNA encoding the RNA-binding protein hnRNP R. Axonal localization of Hnrnpr mRNA and local synthesis of hnRNP R protein are strongly reduced when Ptbp2 is depleted, leading to defective axon growth. Ptbp2 regulates hnRNP R translation by mediating the association of Hnrnpr with ribosomes in a manner dependent on the translation factor eIF5A2. Our data thus suggest a mechanism whereby cytosolic Ptbp2 modulates axon growth by fine-tuning the mRNA transport and local synthesis of an RNA-binding protein. KW - molecular neuroscience KW - RNA-binding proteins KW - RNA transport Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357639 VL - 14 ER - TY - JOUR A1 - Lüffe, Teresa M. A1 - D'Orazio, Andrea A1 - Bauer, Moritz A1 - Gioga, Zoi A1 - Schoeffler, Victoria A1 - Lesch, Klaus-Peter A1 - Romanos, Marcel A1 - Drepper, Carsten A1 - Lillesaar, Christina T1 - Increased locomotor activity via regulation of GABAergic signalling in foxp2 mutant zebrafish – implications for neurodevelopmental disorders JF - Translational Psychiatry N2 - Recent advances in the genetics of neurodevelopmental disorders (NDDs) have identified the transcription factor FOXP2 as one of numerous risk genes, e.g. in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). FOXP2 function is suggested to be involved in GABAergic signalling and numerous studies demonstrate that GABAergic function is altered in NDDs, thus disrupting the excitation/inhibition balance. Interestingly, GABAergic signalling components, including glutamate-decarboxylase 1 (Gad1) and GABA receptors, are putative transcriptional targets of FOXP2. However, the specific role of FOXP2 in the pathomechanism of NDDs remains elusive. Here we test the hypothesis that Foxp2 affects behavioural dimensions via GABAergic signalling using zebrafish as model organism. We demonstrate that foxp2 is expressed by a subset of GABAergic neurons located in brain regions involved in motor functions, including the subpallium, posterior tuberculum, thalamus and medulla oblongata. Using CRISPR/Cas9 gene-editing we generated a novel foxp2 zebrafish loss-of-function mutant that exhibits increased locomotor activity. Further, genetic and/or pharmacological disruption of Gad1 or GABA-A receptors causes increased locomotor activity, resembling the phenotype of foxp2 mutants. Application of muscimol, a GABA-A receptor agonist, rescues the hyperactive phenotype induced by the foxp2 loss-of-function. By reverse translation of the therapeutic effect on hyperactive behaviour exerted by methylphenidate, we note that application of methylphenidate evokes different responses in wildtype compared to foxp2 or gad1b loss-of-function animals. Together, our findings support the hypothesis that foxp2 regulates locomotor activity via GABAergic signalling. This provides one targetable mechanism, which may contribute to behavioural phenotypes commonly observed in NDDs. KW - comparative genomics KW - molecular neuroscience Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264713 VL - 11 ER - TY - JOUR A1 - Rajab, Suhaila A1 - Bismin, Leah A1 - Schwarze, Simone A1 - Pinggera, Alexandra A1 - Greger, Ingo H. A1 - Neuweiler, Hannes T1 - Allosteric coupling of sub-millisecond clamshell motions in ionotropic glutamate receptor ligand-binding domains JF - Communications Biology N2 - Ionotropic glutamate receptors (iGluRs) mediate signal transmission in the brain and are important drug targets. Structural studies show snapshots of iGluRs, which provide a mechanistic understanding of gating, yet the rapid motions driving the receptor machinery are largely elusive. Here we detect kinetics of conformational change of isolated clamshell-shaped ligand-binding domains (LBDs) from the three major iGluR sub-types, which initiate gating upon binding of agonists. We design fluorescence probes to measure domain motions through nanosecond fluorescence correlation spectroscopy. We observe a broad kinetic spectrum of LBD dynamics that underlie activation of iGluRs. Microsecond clamshell motions slow upon dimerization and freeze upon binding of full and partial agonists. We uncover allosteric coupling within NMDA LBD hetero-dimers, where binding of L-glutamate to the GluN2A LBD stalls clamshell motions of the glycine-binding GluN1 LBD. Our results reveal rapid LBD dynamics across iGluRs and suggest a mechanism of negative allosteric cooperativity in NMDA receptors. KW - fluorescence spectroscopy KW - kinetics KW - ligand-gated ion channels KW - molecular neuroscience Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261678 VL - 4 IS - 1 ER - TY - JOUR A1 - Mitjans, M. A1 - Begemann, M. A1 - Ju, A. A1 - Dere, E. A1 - Wüstefeld, L. A1 - Hofer, S. A1 - Hassouna, I. A1 - Balkenhol, J. A1 - Oliveira, B. A1 - Van der Auwera, S. A1 - Tammer, R. A1 - Hammerschmidt, K. A1 - Völzke, H. A1 - Homuth, G. A1 - Cecconi, F. A1 - Chowdhury, K. A1 - Grabe, H. A1 - Frahm, J. A1 - Boretius, S. A1 - Dandekar, T. A1 - Ehrenreich, H. T1 - Sexual dimorphism of \(AMBRA1\)-related autistic features in human and mouse JF - Translational Psychiatry N2 - \(Ambra1\) is linked to autophagy and neurodevelopment. Heterozygous \(Ambra1\) deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of \(AMBRA1\) for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal \(AMBRA1\) genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower \(AMBRA1\) mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by \(in\) \(silico\) analysis. Searching for further autism-relevant characteristics in \(Ambra1^{+/−}\) mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an \(in\) \(vivo\) readout of neuronal excitation–inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of \(AMBRA1/Ambra1\) partial loss-of-function genotypes for female autistic traits. Moreover, they suggest \(Ambra1\) heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism. KW - biology KW - clinical genetics KW - molecular neuroscience Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173782 VL - 2017 IS - 7 ER -