The neurogenic to gliogenic transition of NSPCs

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 rsk inhibitor 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.