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  • In summary our results revealed

    2018-10-20

    In summary, our results revealed that loss of Eva1a leads to impaired NSC self-renewal and differentiation, along with a decrease in autophagy, which is inversely associated with the activation of the PIK3CA/AKT-mTOR signaling. Functionally, EVA1A overexpression or MP treatment substantially rescued Eva1a-depletion-induced NSC self-renewal and neuronal differentiation deficiency, demonstrating the crucial function of EVA1A in embryonic neurogenesis. Our investigations provide insights into the activities of EVA1A, as well as the role of basal autophagy in neurogenesis. Moreover, our results provide a basis for the identification of molecular targets for the treatment of neurodevelopmental disorders caused by dysregulation of autophagy.
    Experimental Procedures
    Author Contributions
    Introduction Primordial germ cox pathway (PGCs) are germ stem cells capable of generating precursors of eggs and sperm and thus offer the basis for reproduction and fertility (Ko et al., 2010; Lin, 2007, 2012). PGC specification demarcates the soma-germline separation and thus sets a balance between individual life and species continuity. PGCs form early in development and migrate into the developing gonad (Wylie, 1999). In adult animals, gonadal germ cells undergo meiosis and produce eggs and sperm. PGC development has been extensively studied in several model organisms including Drosophila, Caenorhabditis elegans, and Xenopus (Houston and King, 2000), zebrafish (Lin et al., 1992; Raz, 2003), and mouse (Hayashi et al., 2011; Ohinata et al., 2005; Saitou et al., 2002; Tam and Zhou, 1996). In these model invertebrates and lower vertebrates, PGCs are cell autonomously preformed by maternally supplied germ plasm, a membrane-less organelle composed mainly of RNA-binding proteins and their mRNAs (Houston and King, 2000; Raz, 2003). In mouse, PGCs are epigenetically induced by cell-cell interactions in the absence of germ plasm (Tam and Zhou, 1996), where signaling molecules such as bone morphogenetic factor 4 play a critical role (Ying et al., 2001). Dozens of genes essential for PGC development are known in the model invertebrates and lower vertebrates (Houston and King, 2000); clearly defined specifiers of the PGC fate has, however, been limited to Drosophila. In this organism, oskar acts as the PGC specifier, as it is necessary for PGC formation and more importantly, sufficient for ectopic PGC induction in a dose-dependent manner (Ephrussi and Lehmann, 1992). However, osk is restricted to certain insects. An evolutionarily conserved gene, piwi, is also necessary for PGC formation and sufficient for tripling the PGC number but incapable of ectopic PGC induction (Megosh et al., 2006). In vertebrates, piwi is dispensable for PGC specification but essential for subsequent PGC development, such as spermatogenesis in mouse (Deng and Lin, 2002), germ cell maintenance in zebrafish (Houwing et al., 2007), and PGC migration in medaka (Li et al., 2012). In mice, blimp1 (encoded by prdm1) and prdm14 are transcriptionally induced by BMP4 in the epiblast at E6.25, which together with tfap2c constitute a tripartite genetic network to induce the PGC fate in vivo (Magnusdottir et al., 2013; Ohinata et al., 2005) and in vitro from embryonic stem (ES) cells (Magnusdottir et al., 2013; Nakaki et al., 2013). In human, SOX17 has most recently been identified as a critical specifier of PGCs in ES cells (Irie et al., 2015). Accumulated data from Drosophila, mouse, and human suggest that PGC specifiers show remarkable diversity and do not follow the evolutionary history, although many genes involved in subsequent germ cell development are highly conserved across animal phyla. A vertebrate-specific germ gene, dead end (dnd), was first identified in zebrafish as a germ plasm component encoding an RNA-binding protein crucial for PGC migration and survival (Tzung et al., 2015; Weidinger et al., 2003). Mouse dnd mutations do not prevent PGC formation (Youngren et al., 2005). The medaka fish (Oryzias latipes) is an excellent model for studying vertebrate development (Wittbrodt et al., 2002), stem cells (Centanin et al., 2011; Hong et al., 1996, 1998b), germ cells, and reproductive technologies. This fish has haploid ES cells capable of whole-animal production by semicloning (Yi et al., 2009), male germ stem cells capable of test-tube production (Hong et al., 2004a), and transgenic lines for PGC visualization (Li et al., 2009; Tanaka et al., 2001). Unusually, maternal germ plasm components distribute widely in medaka (Shinomiya et al., 2000; Xu et al., 2009), rather than locally as in zebrafish (Weidinger et al., 2003; Yoon et al., 1997). This suggests the presence of an unknown key factor that determines the PGC fate. Here we identify Dnd as such a critical PGC specifier in medaka. Interestingly, dnd RNA uses particle formation and partition as a mechanism for asymmetric segregation and cell fate decision in early developing embryos. These results provide insights into our understanding of PGC formation and manipulation in medaka as a lower vertebrate model.