N-cadherin regulates the proliferation and differentiation of ventral midbrain dopaminergic progenitors

Adherens junction (AJ) between dopaminergic (DA) progenitors maintains the structure of ventricular zone and polarity of radial glia cells in the ventral midbrain (vMB) during embryonic development. However, it is unclear how loss of N-cadherin might influence the integrity of the AJ and the process of DA neurogenesis. Here, we used conditional gene targeting approaches to perform the region-specific removal of N-cadherin in the neurogenic niche of DA neurons in the vMB. Removal of N-cadherin in the vMB using Shh-Cre disrupts the AJs of DA progenitors and radial glia processes in the vMB. Surprisingly, loss of N-cadherin in the vMB leads to a significant expansion of DA progenitors, including those expressing Sox2, Ngn2, and Otx2. Cell cycle analyses reveal that the cell cycle exit in the progenitor cells is decreased in the mutants from E11.5 to E12.5. In addition, the efficiency of DA progenitors in differentiating into DA neurons is decreased from E10.5 to E12.5, leading to a marked reduction in the number of DA neurons at E11.5, E12.5, and E17.5. Loss of N-cadherin leads to the diffuse distribution of β-catenin proteins, which are a critical component of AJ and Wnt signaling, from the AJ throughout the entire cytoplasm in neuroepithelial cells, suggesting that canonical Wnt signaling might be activated in the DA progenitors in vMB. Taken together, these results support the notion that N-cadherin regulates the proliferation of DA progenitors and the differentiation of DA neurons through canonical Wnt-β-catenin signaling in the vMB.