Signaling mechanisms involving Wnt/β-catenin and sonic hedgehog (Shh) are known to regulate the development of ventral midbrain (vMB) dopamine neurons. However, the interactions between these two mechanisms and how such interactions can be targeted to promote a maximal production of dopamine neurons are not fully understood. Here we show that conditional mouse mutants with region-specific activation of β-catenin signaling in vMB using the Shh-Cre show a marked expansion of Sox2-, Ngn2-, and Otx2-positive progenitors, but perturbs their cell cycle exit and reduces the generation of dopamine neurons. Furthermore, activation of β-catenin in vMB also results in a progressive loss of Shh expression and Shh target genes. Such antagonistic effects between the activation of Wnt/β-catenin and Shh can be recapitulated in vMB progenitors and in mouse embryonic stem cell cultures. Notwithstanding these antagonistic interactions, cell type-specific activation of β-catenin in the midline progenitors using the Th-IRES-Cre leads to increased dopaminergic neurogenesis. Together, these results indicate the presence of a delicate balance between Wnt/β-catenin and Shh signaling mechanisms in the progression from progenitors to dopamine neurons. Persistent activation of β-catenin in early progenitors perturbs their cell cycle progression and antagonizes Shh expression, whereas activation of β-catenin in midline progenitors promotes the generation of dopamine neurons.

Stem cell-based replacement therapy has emerged as a potential strategy to alleviate specific features of movement disorder in Parkinson's disease. However, the current strategy to produce dopamine (DA) neurons from embryonic stem cells has many limitations, including the difficulty of generating DA neurons with high yields. Further insights into the mechanisms that control the neurogenesis of DA neurons will reduce or mitigate such limitations. It is well established that the ventral midbrain (vMB) contains the neurogenic niche that produces DA neurons. However, it is unclear how the microenvironment within this niche controls DA neurogenesis. Here, we show that β-catenin controls DA neurogenesis by maintaining the integrity of the neurogenic niche and the progression from progenitors to DA neurons. Using conditional gene targeting approaches, we show that regional deletion of β-catenin in the vMB by using Shh-Cre disrupts adherent junctions of progenitors and the integrity of radial glia in the vMB, which leads to a severe reduction in DA neurogenesis and perturbs the migration and segregation of DA neurons. By contrast, Th-IRES-Cre removes β-catenin in a subset of neural progenitor cells without perturbing the cellular and structural integrity of the vMB. Interestingly, loss of β-catenin in Th-IRES-Cre;β-Ctn fl/fl mutants negatively regulates neurogenesis by interfering with the progression of committed progenitors to DA neurons. Taken together, these results provide new insights into the indispensable functions of β-catenin at multiple stages during DA neurogenesis. They also suggest that β-catenin-mediated signaling pathways can be targeted to promote and expand DA neurons in cell-based therapeutic strategies.

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This review addresses our current understanding of the regulatory mechanism by which N-cadherin, a classical cadherin, affects neural progenitor cells (NPCs) during development. N-cadherin is responsible for the integrity of adherens junctions (AJs), which develop in the sub-apical region of NPCs in the neural tube and brain cortex. The apical domain, which contains the sub-apical region, is involved in the switching from symmetric proliferative division to asymmetric neurogenic division of NPCs. In addition, Ncadherin-based AJ is deeply involved in the apico-basal polarity of NPCs and the regulation of Wnt-b-catenin, hedgehog (Hh), and Notch signaling. In this review, we discuss the roles of N-cadherin in the maintenance, proliferation, and differentiation of NPCs through components of AJ, b-catenin and aE-catenin.