Svetoni Francesca, De Paola Elisa, La Rosa Piergiorgio, Mercatelli Neri, Caporossi Daniela, Sette Claudio, Paronetto Maria Paola
Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", 00135 Rome, Italy.
Laboratories of Cellular and Molecular Neurobiology and of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy.
Hum Mol Genet. 2017 Jul 15;26(14):2732-2746. doi: 10.1093/hmg/ddx160.
Brain development involves proliferation, migration and specification of neural progenitor cells, culminating in neuronal circuit formation. Mounting evidence indicates that improper regulation of RNA binding proteins (RBPs), including members of the FET (FUS, EWS, TAF15) family, results in defective cortical development and/or neurodegenerative disorders. However, in spite of their physiological relevance, the precise pattern of FET protein expression in developing neurons is largely unknown. Herein, we found that FUS, EWS and TAF15 expression is differentially regulated during brain development, both in time and in space. In particular, our study identifies a fine-tuned regulation of FUS and EWS during neuronal differentiation, whereas TAF15 appears to be more constitutively expressed. Mechanistically FUS and EWS protein expression is regulated at the post-transcriptional level during neuron differentiation and brain development. Moreover, we identified miR-141 as a key regulator of these FET proteins that modulate their expression levels in differentiating neuronal cells. Thus, our studies uncover a novel link between post-transcriptional regulation of FET proteins expression and neurogenesis.
大脑发育涉及神经祖细胞的增殖、迁移和分化，最终形成神经元回路。越来越多的证据表明，包括FET（FUS、EWS、TAF15）家族成员在内的RNA结合蛋白（RBPs）调控不当会导致皮质发育缺陷和/或神经退行性疾病。然而，尽管它们具有生理相关性，但FET蛋白在发育中的神经元中的精确表达模式在很大程度上仍不清楚。在此，我们发现FUS、EWS和TAF15的表达在大脑发育过程中在时间和空间上均受到差异调控。特别是，我们的研究确定了神经元分化过程中FUS和EWS的微调调控，而TAF15似乎表达更为恒定。从机制上讲，FUS和EWS蛋白表达在神经元分化和大脑发育过程中在转录后水平受到调控。此外，我们确定miR-141是这些FET蛋白的关键调节因子，可调节它们在分化神经元细胞中的表达水平。因此，我们的研究揭示了FET蛋白表达的转录后调控与神经发生之间的新联系。
