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    • FOXP labels striatal precursors and differentiated MSNs Dell

    2018-10-20

    FOXP1 labels striatal precursors and differentiated MSNs (Delli et al., 2013). Diverse studies thus far have attempted to pre-differentiate stem cycloheximide solubility into transplantable striatal progenitors or MSNs by using various kinds of differentiation protocols. Human ESCs were demonstrated to terminally differentiate into GABAergic DARPP32-positive neurons in vitro and in vivo by the use of sonic hedgehog and BDNF as key molecules (Aubry et al., 2008; Ma et al., 2012). Therefore, our approach with mouse ESCs was to analyze whether very early PSA-NCAM-positive neural progenitors, which expressed one of the earliest telencephalic markers FOXG1, could differentiate in vivo into MSNs through continuous BDNF supply. To obtain NPCs, we used the differentiation protocol of Bernreuther et al. (2006) with minor modifications. This study used mouse ESC-derived L1-overexpressing NPCs in QA-lesioned mice, which led to short-term functional improvement. Here, we show that functional improvement was accompanied by increased striatal differentiation of BDNF NPCs, meaning that BDNF as signaling molecule is sufficient to trigger in vivo differentiation into MSNs. Likewise, for in vitro striatal differentiation of human ESCs, alternatively the potent telencephalic morphogen sonic hedgehog could be used at early stages of differentiation to obtain MSNs after transplantation (Danjo et al., 2011). In addition to the analysis of in vivo differentiation of transplanted cells, precursor proliferation of endogenous DCX-positive cells was investigated as a potential mechanism leading to improved motor behavior. It is known that striatal QA lesion by itself induces proliferation and migration of adult neuronal stem cells from the dorsal SVZ as an attempt to regenerate the lesioned striatum (Tattersfield et al., 2004). BDNF is known to be an important trigger of adult neurogenesis (Vilar and Mira, 2016). Therefore, transplantation of BDNF-expressing cells could induce a higher migration rate, better survival, increased proliferation, and/or differentiation of SVZ precursor cells. However, we found no difference in the number of DCX-positive cells in QA-lesioned animals with or without BDNF cell transplants, which implies that BDNF exerted no positive effect on endogenous progenitors. Interestingly, GFP transplants significantly reduced the number of DCX cells. In conclusion, this would mean that NPC transplantation by itself induces negative changes in tissue homeostasis or endogenous regeneration, which might be overcome by BDNF. The differences in the motoric outcome after transplantation of both cell types could hence be due to a combination of BDNF-positive effects on differentiation of transplanted cells and its preserving effects on lesion-induced SVZ neurogenesis.
    Experimental Procedures For a more detailed description, see Supplemental Experimental Procedures.
    Author Contributions
    Acknowledgments This work was partly funded by the University of Mainz (Stufe I funding). We thank Andrea Conrad, Ruth Jelinek, and Marcus Keil for excellent technical assistance.
    Introduction Neurogenesis occurs in the subgranular zone (SGZ) of the dentate gyrus (DG) throughout life in the adult brain of most mammals including human beings (Bond et al., 2015; Eriksson et al., 1998; Spalding et al., 2013). Newly generated neurons can be integrated into the pre-existing neural circuits (Ge et al., 2007; Lledo et al., 2006; Restivo et al., 2015; Sultan et al., 2015; Tashiro et al., 2006a; van Praag et al., 2002). Although the physiological roles of newborn neurons are not fully understood, many studies indicated that they were involved in the hippocampus-dependent functions such as learning and memory, mood regulation, and pattern separation (Christian et al., 2014; Clelland et al., 2009; Deng et al., 2010; Kang et al., 2016; Sahay et al., 2011a, 2011b; Shors et al., 2001). The process of neurogenesis in the adult brain consists of several stages including proliferation, differentiation, migration, survival, axonal and dendritic targeting, and synaptic integration (Ehninger and Kempermann, 2008). Intense efforts were conducted in the past several years to dissect how the different stages of neurogenesis were regulated (Bond et al., 2015). Physical activities such as exercise and an enriched environment can prompt neurogenesis (Marlatt et al., 2013; Nilsson et al., 1999; Valero et al., 2011; van Praag et al., 1999). Stress, aging, and neurological disorders, however, may inhibit neurogenesis (Richetin et al., 2015; Winner et al., 2011; Yun et al., 2010; Zhao et al., 2008).