Abstract
Dysregulated expression of miR-219, a brain-specific microRNA, has been observed in neurodevelopmental disorders, such as schizophrenia (SCZ). However, its role in normal mammalian neural stem cells (NSCs) and in SCZ pathogenesis remains unknown. We show here that the nuclear receptor TLX, an essential regulator of NSC proliferation and self-renewal, inhibits miR-219 processing. miR-219 suppresses mouse NSC proliferation downstream of TLX. Moreover, we demonstrate upregulation of miR-219 and downregulation of TLX expression in NSCs derived from SCZ patient iPSCs and DISC1-mutant isogenic iPSCs. SCZ NSCs exhibit reduced cell proliferation. Overexpression of TLX or inhibition of miR-219 action rescues the proliferative defect in SCZ NSCs. Therefore, this study uncovers an important role for TLX and miR-219 in both normal neurodevelopment and in SCZ patient iPSC-derived NSCs. Moreover, this study reveals an unexpected role for TLX in regulating microRNA processing, independent of its well-characterized role in transcriptional regulation.
Highlights
Dysregulated expression of miR-219, a brain-specific microRNA, has been observed in neurodevelopmental disorders, such as schizophrenia (SCZ)
Because TLX is a transcription factor, we examined the level of primary transcripts of miR-219. miR-219 is derived from two primary transcripts, pri-miR-219-1 and pri-miR-219-2
In this study, we have demonstrated that TLX regulates miRNA processing independent of its well-characterized role in transcriptional regulation, and that miR-219 acts downstream of TLX to regulate neural stem cells (NSCs) proliferation and differentiation in mammalian brains
Summary
Both Drosha and DGCR8 were detected in the TLX immunocomplex (Fig. 2d) These results indicate that TLX interacts with components of the miRNA processing machinery. The interaction of TLX with Drosha and DGCR8 led us to hypothesize that TLX could inhibit miR-219 processing by preventing the miRNA processing machinery from binding to pri-miR-219 To test this hypothesis, we made cell lysates from NSCs transduced with lentivirus expressing TLX siRNA a Transfect HA-TLX to HeLa Make nuclear extracts IP with αHA SDS–PAGE SimplyBlue staining. Treatment with miR-219 increased the percentage of bIII tubulin (Tuj1)-positive neurons substantially, compared to treatment with a control RNA (Fig. 3b,d) These results indicate that miR-219 promotes mammalian NSC differentiation into neurons. Compared to control RNA-transfected cells, substantially more a b
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
