The neurogenic to gliogenic transition of NSPCs is

The neurogenic-to-gliogenic transition of NSPCs is probably governed by a multi-layered system. The epigenetic status of astrocyte-specific (Takizawa et al., 2001) and neurogenic genes changes during development (Hirabayashi et al., 2009; Kishi et al., 2012; Pereira et al., 2010), critically determining NSPC responsiveness to extrinsic differentiation signals. Several transcription factors regulate the acquisition of gliogenic competence. For example, nuclear factor IA (NFIA) acts as a key regulator for the initiation of gliogenesis (das Neves et al., 1999; Deneen et al., 2006; Kang et al., 2012). Nfia is induced by the high-mobility group (HMG) box family member SOX9 and forms a SOX9/NFIA complex to control the induction of a subset of glial-specific genes (Kang et al., 2012). Moreover, NFIA is required for Notch signaling-induced demethylation of the glial fibrillary acidic protein (Gfap) gene promoter in NSPCs (Namihira et al., 2009). Our group has reported previously that chicken ovalbumin upstream promoter-transcription factor (COUP-TF) I and COUP-TFII are triggers of the neurogenic-to-gliogenic competence switch in NSPCs (Naka et al., 2008). However, in vitro knockdown (KD) of Coup-tfI/II in NSPCs did not substantially affect the aa-utp levels of Nfia (Naka et al., 2008). Therefore, multiple transcriptional regulatory cascades act together to control NSPC acquisition of gliogenic competence. MicroRNAs (miRNAs) are small endogenous non-coding RNAs found in many different organisms, including animals that regulate gene expression mainly at the post-transcriptional level (Bartel, 2004). In vertebrates, miRNAs base-pair with target sequences typically located within the 3′ UTR of target mRNAs by using 5′ “seed” regions. Furthermore, miRNAs stimulate RNA-silencing complexes to induce degradation, destabilization, and/or translational inhibition of target mRNAs (Bartel, 2009; Guo et al., 2010; Huntzinger and Izaurralde, 2011) and are seemingly involved in almost all cellular events, including the determination of cell fate (Ebert and Sharp, 2012; Friedman et al., 2009). In the developing mammalian CNS, various miRNAs participate in the control of neural stem cell self-renewal, proliferation, and differentiation (Balzer et al., 2010; Cimadamore et al., 2013; Li and Jin, 2010; Naka-Kaneda et al., 2014; Neo et al., 2014; Qureshi and Mehler, 2012; Shibata et al., 2011; Visvanathan et al., 2007; Yoo et al., 2009; Zhao et al., 2009). This study identifies miR-153 as a regulator of the initiation of gliogenesis in the developing CNS. Although miR-153 is implicated in synaptic function, neurodegenerative disorders, and fetal ethanol exposure (Chi et al., 2009; Doxakis, 2010; Liang et al., 2012; Tsai et al., 2014; Wei et al., 2013), no reports to date have described a function for miR-153 in gliogenesis by NSPCs. Here we demonstrate that miR-153 inhibits the acquisition of gliogenic competence in NSPCs by targeting Nfia/b mRNAs.
Results
Discussion Here we demonstrated that miR-153 plays a crucial role in the regulation of acquisition of gliogenic competence by NSPCs as an upstream regulator of NFIA/B. The inverse correlation of miR-153 and NFIA/B expression revealed here is indicative of the requirement of miR-153 for the prevention of gliogenesis by NSPCs in the early neurogenic period and strongly suggests that the regulation of NFIA/B expression levels by miR-153 is one of the critical factors for the timing of astrogliogenesis (Figure 7). Importantly, miR-153 has been shown to be able to regulate the expression of NFIA/B in the immature brain during the course of this study (Tsai et al., 2014). However, the spatiotemporal expression of miR-153 in the developing CNS, the LOF analysis of miR-153 to clarify its physiological function in the developing CNS, and the association of miR-153 with astrogliogenesis have not been reported.