TY  - JOUR
A1  - Ghanawi, Hanaa
A1  - Hennlein, Luisa
A1  - Zare, Abdolhossein
A1  - Bader, Jakob
A1  - Salehi, Saeede
A1  - Hornburg, Daniel
A1  - Ji, Changhe
A1  - Sivadasan, Rajeeve
A1  - Drepper, Carsten
A1  - Meissner, Felix
A1  - Mann, Matthias
A1  - Jablonka, Sibylle
A1  - Briese, Michael
A1  - Sendtner, Michael
T1  - Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin
JF  - Nucleic Acids Research
N2  - Neurons critically rely on the functions of RNA-binding proteins to maintain their polarity and resistance to neurotoxic stress. HnRNP R has a diverse range of post-transcriptional regulatory functions and is important for neuronal development by regulating axon growth. Hnrnpr pre-mRNA undergoes alternative splicing giving rise to a full-length protein and a shorter isoform lacking its N-terminal acidic domain. To investigate functions selectively associated with the full-length hnRNP R isoform, we generated a Hnrnpr knockout mouse (Hnrnpr\(^{tm1a/tm1a}\)) in which expression of full-length hnRNP R was abolished while production of the truncated hnRNP R isoform was retained. Motoneurons cultured from Hnrnpr\(^{tm1a/tm1a}\) mice did not show any axonal growth defects but exhibited enhanced accumulation of double-strand breaks and an impaired DNA damage response upon exposure to genotoxic agents. Proteomic analysis of the hnRNP R interactome revealed the multifunctional protein Yb1 as a top interactor. Yb1-depleted motoneurons were defective in DNA damage repair. We show that Yb1 is recruited to chromatin upon DNA damage where it interacts with gamma-H2AX, a mechanism that is dependent on full-length hnRNP R. Our findings thus suggest a novel role of hnRNP R in maintaining genomic integrity and highlight the function of its N-terminal acidic domain in this context.
KW  - nuclear ribonucleoprotein-R
KW  - determining gene-product
KW  - actin messenger RNA
KW  - comet assay
KW  - genome wide
KW  - spinal cord
KW  - YB-1
KW  - SMN
KW  - interacts
KW  - enrichment
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265687
VL  - 49
IS  - 21
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  -