Date Published: July 12, 2017
Publisher: Public Library of Science
Author(s): Valentina Tosetti, Jenny Sassone, Anna L. M. Ferri, Michela Taiana, Gloria Bedini, Sara Nava, Greta Brenna, Chiara Di Resta, Davide Pareyson, Anna Maria Di Giulio, Stephana Carelli, Eugenio A. Parati, Alfredo Gorio, Jean-Marc A Lobaccaro.
The complex architecture of adult brain derives from tightly regulated migration and differentiation of precursor cells generated during embryonic neurogenesis. Changes at transcriptional level of genes that regulate migration and differentiation may lead to neurodevelopmental disorders. Androgen receptor (AR) is a transcription factor that is already expressed during early embryonic days. However, AR role in the regulation of gene expression at early embryonic stage is yet to be determinate. Long non-coding RNA (lncRNA) Sox2 overlapping transcript (Sox2OT) plays a crucial role in gene expression control during development but its transcriptional regulation is still to be clearly defined. Here, using Bicalutamide in order to pharmacologically inactivated AR, we investigated whether AR participates in the regulation of the transcription of the lncRNASox2OTat early embryonic stage. We identified a new DNA binding region upstream of Sox2 locus containing three androgen response elements (ARE), and found that AR binds such a sequence in embryonic neural stem cells and in mouse embryonic brain. Our data suggest that through this binding, AR can promote the RNA polymerase II dependent transcription of Sox2OT. Our findings also suggest that AR participates in embryonic neurogenesis through transcriptional control of the long non-coding RNA Sox2OT.
In the developing telencephalon, a large number of neurons originate from neuroepithelial cells and migrate across telencephalic regions. This occurs at approximately between embryonic day (E) E10.5 and E12 in mice when neuroepithelial cells transform into radial glia cells that possess neural stem cells (NSCs)/progenitor cells features [1–3]. This process is tightly regulated at transcriptional level and abnormal gene expression lead to severe neurodevelopmental disorders such as autism spectrum disorders, seizure disorders, and intellectual disability [4–6]. Thus, the understanding of molecular mechanisms that control gene expression in the earliest stages of neurogenesis (E10-E12) is crucial to elucidate the etiology of neurodevelopmental diseases.
The present study shows that AR is expressed in embryonic NSCs and E12.0 forebrains, first describe a novel androgen response element (ARE) located at Sox2OT gene and show that AR binds the Sox2OT transcript in E12.0 forebrains and embryonic NSCs.