Multiple roles of beta-catenin in controlling the neurogenic niche for midbrain 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 beta-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 beta-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 beta-catenin in a subset of neural progenitor cells without perturbing the cellular and structural integrity of the vMB. Interestingly, loss of beta-catenin in Th-IRES-Cre;beta-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 beta-catenin at multiple stages during DA neurogenesis. They also suggest that beta-catenin-mediated signaling pathways can be targeted to promote and expand DA neurons in cell-based therapeutic strategies.
VA Medical Center and Department of Pathology, University of California San Francisco, San Francisco, CA 94121, USA.
Mianzhi
M
Tang
Yasunori
Y
Miyamoto
Eric J
EJ
Huang
D022005:Adherens Junctions / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D008636:Mesencephalon / Q000196:embryology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D055495:Neurogenesis; D009457:Neuroglia / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D055153:Stem Cell Niche; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000502:physiology*
D051176:beta Catenin; D004298:Dopamine