Journal Article

TDP-43 Regulates the Microprocessor Complex Activity During In Vitro Neuronal Differentiation

Ballarino, Monica, Bozzoni, Irene, Dini Modigliani, Stefano, Grossi, Elena, Laneve, Pietro, Morlando, Mariangela, Caffarelli, Elisa, Di Carlo, Valerio

2013

Overview

TDP-43 (TAR DNA-binding protein 43) is an RNA-binding 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. TDP-43 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 required for the Drosha-mediated regulation of Neurogenin 2 , a master gene orchestrating neurogenesis, whereas post-transcriptional 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.

• Publisher: Springer US,Springer Nature B.V
• Subject: Basic Helix-Loop-Helix Transcription Factors - metabolism / Biomedical and Life Sciences / Biomedicine / Brain / Cell Biology / Cell Differentiation - drug effects / Cell Differentiation - genetics / Cell Line, Tumor / DNA-Binding Proteins - metabolism / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic - drug effects / Gene Knockdown Techniques / Humans / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / Models, Biological / Nerve Tissue Proteins - metabolism / Neurobiology / Neuroblastoma - genetics / Neuroblastoma - pathology / Neurology / Neurons / Neurons - cytology / Neurosciences / Proteasome Inhibitors - pharmacology / Protein Binding - drug effects / Protein Binding - genetics / Proteins / Proteins - metabolism / Ribonuclease III - genetics / Ribonuclease III - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / RNA-Binding Proteins