**4. Role of Wnt/β-catenin signaling in DA neural plasticity or repair in adulthood**

The Wnt/β-catenin signaling pathway also actively functions in neural plasticity and repair of DA neurons in the midbrain of disease conditions Interestingly, the crosstalk between Wnt/β-catenin signaling and inflammatory was observed in plasticity of subventricular zone progenitors in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD, suggesting its involvement in consequences for neuroprotection and functional repair [30]. Accumulating evidence indicated that a population of astrocyte was functionally acti‐ vated, named reactive astrocytes with active proliferation, morphological expanding of cell bodies and increasing generation of various neurotrophic factors, and with predominate dis‐ tribution in the nigra and striatum of PD condition. These reactive astrocytes and Wnt/β-cat‐ enin signaling showed a link of nigrostriatal injury to repair in MPTP model of PD. The Wnt signaling components Frizzled-1 and β-catenin were dynamically regulated in response to MPTP insult-induced DA neuronal degeneration and reactive glial activation. Activated or reactive astrocytes in the ventral midbrain were identified as candidate source of Wnt1. Blocking Wnt/Fzd signaling with Dkk1 also counteracted astrocyte-induced neuroprotection against MPP (+) toxicity in primary mesencephalic astrocyte-neuron cultures. Moreover, as‐ trocyte-derived Wnt1 promoted DA neurogenesis from adult midbrain stem cells or progen‐ itor cells. Conversely, lack of Wnt1 transcription in response to MPTP in aged animals and failure of DA neurons to recover could be reversed by activation of Wnt/β-catenin signaling *in vivo*, suggesting MPTP-reactive astrocytes and Wnt1 worked as neuroprotective activity in DA neural plasticity [31]. Obviously, Wnt1 regulated Frizzled-1/β-catenin signaling path‐ way as a candidate regulatory circuit for DA neuron-astrocyte crosstalk in the ventral mid‐ brain, also implying that Wnt signals might act as the critical messages in neuron-glial intercommunication in the adult mammalian nervous system [32].

catenin signaling is a key regulator of proliferation and differentiation of DA precursors and

Dynamic temporal and cell type-specific expression of Wnt signaling components was found in the developing midbrain [15]. The DA neuronal cluster size was determined dur‐ ing early forebrain patterning [16]. Furthermore, temporally controlling modulation of FGF/ERK signaling directed midbrain DA neural progenitor fate in mouse and human pluri‐ potent stem cells [17]. Dickkopf-1 (Dkk1), a specific Wnt signaling inhibitor, regulated ven‐ tral midbrain DA neuronal differentiation and morphogenesis [18]. Blockade of Wnt/βcatenin signaling pathway promoted neuronal induction and DA-phenotype differentiation in embryonic stem cells [19]. Delayed DA neuron differentiation was seen in the Lrp6 mu‐ tant mice [20]. Signaling interactions between Wnt/β-catenin and sonic hedgehog (Shh) mechanisms functioned to regulate the production of DA neurons. Specific deletion of intra‐ cellular β-catenin in Shh expressing cells resulted in diminished DA progenitors, NgN2, BrdU labeling cells, and subsequently DA neurons. Permanent stabilization of β-catenin in Shh expressing cells led to more DA progenitors and DA neurons accordingly, and inhibi‐ tion of GSK-3β also increases the differentiation of DA precursors [21]. HPRT deficiency co‐ ordinately dysregulated canonical Wnt signaling in neuro-developmental regulatory process [22]. Wnts showed antagonism of Shh signaling pathway and facilitated neurogene‐ sis in the midbrain floor plate [23]. The β-arrestin was also a necessary component of Wnt/ beta-catenin signaling linking Dvl and axin *in vitro* and *in vivo* functions [24]. Wnt5a induced the DA differentiation of midbrain neural stem cells *in vitro*, and the effect was mediated by the phosphorylation of Dishevelled protein and activation of GTPase RAC1. Wnt5A stimu‐ lated the GDP/GTP exchange at pertussis toxin-sensitive heterotrimeric G proteins [25]. As to Wnt receptors, mutation of Lrp6 might not affect the patterning; proliferation and cell death in the ventral midbrain, but displayed a delay in the onset of DA precursor differen‐ tiation. Lrp6(-/-) mice exhibited 50% reduction in DA neurons and expression of DA mark‐ ers such as Nurr1 and Pitx3 as well as a defect in midbrain morphogenesis in the mutant embryos at E11.5. The extracellular domain of Lrp5/6 inhibited the non-canonical Wnt sig‐ naling *in vivo* condition [26]. The mitogen-activated protein kinases promoted Wnt/β-catenin signaling via phosphorylation of LRP6 [27]. Ectopic Wnt/β-catenin signaling was also in‐ volved in induction of neurogenesis in spinal cord [28]. In addition, Wnt5a was required for the endothelial differentiation of embryonic stem cells and vascularization via both Wnt/β-

different Wnts might have specific and unique activity profiles during DA neurogenesis.

144 Trends in Cell Signaling Pathways in Neuronal Fate Decision

catenin signaling and protein kinase C pathways [29].

**adulthood**

**4. Role of Wnt/β-catenin signaling in DA neural plasticity or repair in**

The Wnt/β-catenin signaling pathway also actively functions in neural plasticity and repair of DA neurons in the midbrain of disease conditions Interestingly, the crosstalk between Wnt/β-catenin signaling and inflammatory was observed in plasticity of subventricular zone progenitors in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD, suggesting its involvement in consequences for neuroprotection and functional repair Moreover, The Wnt/β-catenin signaling also involved in Parkin protection of DA neurons [33]. Differential expression of Wnts was observed after spinal cord contusion injury in adult ro‐ dents [34]. Wnt signaling in the activated microglia; cells exhibited proinflammatory effect. Gene-expression profiling revealed that Wnt3A specifically increased expression of proinflam‐ matory immune response genes in microglia and exacerbated release of IL-6, IL-12, and tumor necrosis factor α [35]. Heterotrimeric G protein-dependent Wnt5A signaling to ERK1/2 mediat‐ ed distinct aspects of proinflammatory transformation in microglial cells [36]. While combin‐ ing nitric oxide release with anti-inflammatory activity preserved DA innervation and prevented motor impairment in the MPTP model of PD [37], switching the microglial harmful phenotype promoted lifelong restoration of DA neurons from inflammatory degeneration in the substantia nigra of aged mice [38]. In addition, activation or inhibition of Wnt/β-catenin sig‐ naling could regulate neuronal and glial differentiation in neurospheres, respectively. Inhibi‐ tion of Wnt signaling promoted gliogenesis from neural stem cells. Long-term activation of Wnt signaling pathway by Wnt-7a or GSK3 inhibitors promoted a moderate increase of neuro‐ nal differentiation and blocked gliogenesis. In contrast, Wnt pathway inhibition by Dkk1overexpression robustly increased gliogenesis [39]. Accumulating evidences suggested that the glial cells including reactive astrocytes and microglial cells might present as crucial turning points for the therapeutic strategy against PD [40, 41]
