TDP-43 Regulates the Microprocessor Complex Activity During In Vitro Neuronal Differentiation
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TDP-43 Regulates the Microprocessor Complex Activity During In Vitro Neuronal Differentiation Valerio Di Carlo & Elena Grossi & Pietro Laneve & Mariangela Morlando & Stefano Dini Modigliani & Monica Ballarino & Irene Bozzoni & Elisa Caffarelli
Received: 13 June 2013 / Accepted: 22 September 2013 / Published online: 11 October 2013 # Springer Science+Business Media New York 2013
Abstract TDP-43 (TAR DNA-binding protein 43) is an RNAbinding protein implicated in RNA metabolism at several levels. Even if ubiquitously expressed, it is considered as a neuronal activity-responsive factor and a major signature for neurological pathologies, making the comprehension of its activity in the nervous system a very challenging issue. TDP43 has also been described as an accessory component of the Drosha–DGCR8 (DiGeorge syndrome critical region gene 8) microprocessor complex, which is crucially involved in basal and tissue-specific RNA processing events. In the present study, we exploited in vitro neuronal differentiation systems to investigate the TDP-43 demand for the microprocessor function, focusing on both its canonical microRNA biosynthetic activity and its alternative role as a post-transcriptional regulator of gene expression. Our findings reveal a novel role for TDP-43 as an essential factor that controls the stability of Drosha protein during neuronal differentiation, thus globally affecting the production of microRNAs. We also demonstrate that TDP-43 is Electronic supplementary material The online version of this article (doi:10.1007/s12035-013-8564-x) contains supplementary material, which is available to authorized users. V. Di Carlo : E. Grossi : M. Morlando : S. Dini Modigliani : M. Ballarino : I. Bozzoni Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy I. Bozzoni : E. Caffarelli (*) Institute of Molecular Biology and Pathology, CNR, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy e-mail: [email protected]
required for the Drosha-mediated regulation of Neurogenin 2, a master gene orchestrating neurogenesis, whereas posttranscriptional control of Dgcr8, another Drosha target, resulted to be TDP-43-independent. These results implicate a previously uncovered contribution of TDP-43 in regulating the abundance and the substrate specificity of the microprocessor complex and provide new insights into TDP-43 as a key player in neuronal differentiation. Keywords Drosha . Microprocessor . miRNAs . Neurogenin 2 . Neuronal differentiation Abbreviations TDP-43 ALS FTLD DGCR8 miRNA or miR Neurog2 Ngn2 Neurog2 NB RA siRNA mRNA qRT-PCR RT-PCR
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy
UTR RIP FUS GAPDH
V. Di Carlo : I. Bozzoni Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
SCARNA17 snRNA
P. Laneve : I. Bozzoni : E. Caffarelli
TAR DNA-binding protein 43 Amyotrophic lateral sclerosis Frontotemporal lo
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