**5. Prospect on manipulation of Wnt/β-catenin signaling for regeneration medicine**

The studies have indicated that transplantation of Wnt primed neural stem cells might result in improvements of cellular and functional recovery in PD condition. The midbrain neural stem cells with Wnt5a-treatment showed beneficial effect for DA cell replacement therapy in parkinsonian animal model [42], and purified Wnt5a increased dishevelled phosphorylation and DA neuronal differentiation in the midbrain [43]. Both GSK-3β inhibition and β-catenin stabilization increased commitment into DA neurons of neural precursors in the ventral midbrain [44], and the application of GSK-3β inhibitor lithium also influenced DA differen‐ tiation potential of human NT2 cells [45]. Generation of DA phenotype in neural stem cells could be carried out by engineering Nurr1 and Wnt signals [46]. Wnts also showed regulat‐ ing role on differentiation of noradrenergic neuronal precursors in locus coeruleus [47]. In addition, the functional involvement of Wnt/β-catenin signaling pathway in link of reactive astrocytes and plasticity or repair of nigrostriatal system further suggests Wnt/β-catenin sig‐ naling as neuroprotection therapeutic targets [30, 31]. It is hopefully that DA differentiation of the neural stem cells and the nigrostriatal plasticity may be effectively and specifically en‐ hanced or improved by manipulation targeting on Wnt/β-catenin signaling pathway [48].

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#### **6. Summary**

Although the DA neuronal cell commitment from neural stem cells or progenitor cells is highly complicated and precisely regulated process, the canonical Wnt/β-catenin pathway shows a critical role in controlling differentiation of DA neurons in the ventral midbrain during development and plasticity or neural repair in adulthood. In addition, Wnt singling might also act via Ca2+, JNK signaling and function candidate messages in DA neuron-glial cross-talk as well. Taken together, it is hopefully expected that molecular target manipula‐ tion of Wnt/β-catenin signaling cascades will benefit controlling of DA neurogenesis and es‐ tablishing novel cell therapy for PD in human beings.
