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  • The leading approaches to this are DA cell


    The leading approaches to this are DA cell transplantation, or stimulating endogenous DA neurogenesis, in either SNc or its sirtuin 1 efferent target the dorsal striatum. Despite progression of cell transplantation to clinical trials, it is still not widely available due to lack of a standardized and morally acceptable source of transplantable cells, immunological reaction, teratoma formation, and failure of transplanted sirtuin 1 to acquire and maintain the DA phenotype (Rao, 2001). Stimulating endogenous SNc DA neurogenesis may overcome many of these obstacles, however most studies have shown proliferating cells here either remain undifferentiated, or differentiate into glia, not neurons (Cooper and Isacson, 2004; Frielingsdorf et al., 2004; Yoshimi et al., 2005a,b; Aponso et al., 2008), but see Zhao et al. (2003). Nevertheless, the presence of cell renewal in the adult SNc engenders some hope, particularly since it was shown that new cells harvested from the adult rat SNc can generate neurons if they are provided appropriate environmental cues in vitro and in the adult hippocampus, an established neurogenic niché (Lie et al., 2002). Also, another study has reported evidence that a particular sub-class of Nestin-expressing (Nestin+) neural precursor cells (NPCs) in the normal and 1-methyl-4-phyenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated SNc, have a propensity to generate new neurons in situ (Shan et al., 2006). It is possible that neurogenesis from Nestin+ cells was overlooked in the majority of midbrain neurogenesis studies because Nestin+ cells can be slowly or latently proliferating type-1 stem cells and therefore not incorporate much BrdU (Kempermann, 2011). Furthermore, Shan et al. (2006) could not determine the full extent of neuronal differentiation from Nestin+ cells because they could only identify Nestin-expressing cells whilst Nestin expression was occurring, i.e. they could not perform long-term lineage tracing. Given the importance for progressing DA cell replacement therapies for the motor symptoms of PD, the present study sought to confirm and extend the findings of Shan et al. (2006). An important difference between the present study and that of Shan et al. (2006) is we used transgenic mice permitting permanent reporter expression in adult Nestin+ cells and their progeny, and thus long-term lineage tracing of adult Nestin+ cells.
    Materials & methods
    Discussion Here we report the existence of large numbers of cells in the adult mouse midbrain that ought to derive from adult Nestin-expressing cells. In some respects our findings (discussed below) support the notion that these cells are a product of classical adult neurogenesis, and that Nestin+ NPCs might differentiate into neurons in situ, albeit very slowly. However, our findings also suggest the possibility that a panoply of genes traditionally considered as ‘neurogenic’ (e.g. Nestin & Sox2 in the present study) can be expressed by mature midbrain neurons in some, as yet unknown context. If so, interpreting neurogenesis in the adult midbrain on the basis of Nestin expression is problematic, which has implications for future PD research. Our suggestion that mature midbrain neurons express immature or neurogenic genes is based on the following: (1) At the earliest time-points following tamoxifen (i.e. 4-days) β-gal+ or eYFP+ midbrain cells had mature neuronal morphologies and were immunoreactive against NeuN. It would be very surprising if this was enough time for Nestin+ NPCs to become mature neurons, particularly in adult midbrain which is generally considered to be inhibitory for neurogenesis (Lie et al., 2002). Even in the established neurogenic niches (i.e. LV, RMS, OB and hippocampal SGZ) this process takes 7–8weeks (Jessberger and Kempermann, 2003; Kempermann, 2011), and in the present study our single-cell PCR data suggest up-regulation of mature neuronal genes in β-gal+ or eYFP+ midbrain cells occurs over a timeframe of several months, not days (Fig. 6c). (2) ‘Leaky’ transgene expression, i.e. β-gal or eYFP expression in the absence of Nestin expression or Cre-LoxP recombination, is an established problem with the Cre-LoxP system and is a likely source of β-gal+ or eYFP+ mature neurons soon after tamoxifen administration in our mice. However, we do not think this is the complete explanation because some β-gal+ cells with mature neuronal morphology expressed Sox2 soon after tamoxifen (Fig. 3g–n). Sox2 and Nestin are closely functionally aligned as stem cell markers in adult neurogenesis (Kempermann, 2011), so it is unclear why ‘leaky’ β-gal expression, i.e. in the absence of Nestin expression, would also produce Sox2 expression. Furthermore, in another recent study from our laboratory we determined that many eYFP+ cells in NesCreERT2/R26eYFP mice at early time-points following tamoxifen are mature neurons, defined electrophysiologically, despite the fact that they also uniquely (compared to neighbouring eYFP− neurons) express Pax6, Ngn2 and/or Msx1 [determined by single-cell PCR of a sample of the cell\'s cytoplasm harvested immediately following electrophysiological characterization (Farzanehfar, 2016)]. Thus we conclude that Nestin is expressed by some mature neurons in the adult midbrain, as has been reported in basal forebrain, hippocampus and striatum in adult rat and human brain (Hendrickson et al., 2011). This possibility warrants further investigation including interrogation of functional context. For example, does it reflect cell de- or re-differentiation that has occurred in tissues outside the adult central nervous system (Echeverri et al., 2002; Bonventre and Bonventre, 2003; Zhang et al., 2010; Zheng et al., 2011), or previously unknown functions of these genes, or simply non-functional gene expression?