Foxa2 단백의 중뇌 흑질 도파민 신경세포 분화, 기능 및 생존력 증진 효과

Abstract

Function of the forkhead transcription factor Foxa2 has recently been reported in midbrain dopamine neuronal development. In this study, gain-of-function of this factor drives neural precursors isolated from diverse brain regions of mice and rats to differentiate towards nigral (A9)-type midbrain dopamine neurons. Foxa2 is involved in multiple aspects of dopamine neuron differentiation, including dopamine phenotype acquisition, midbrain-specific gene expression, and neuronal maturation. Interestingly, Foxa2 cooperates with Nurr1, another transcription factor specifically involved in midbrain dopamine neuron development. Co-expression of the two factors efficiently induced differentiation of neural precursors into dopamine neurons that reversed motor deficits when grafted to a rat model of Parkinson’s disease. Dopamine neurons generated from precursors in response to Foxa2 overexpression were relatively resistant to toxins. Furthermore, Foxa2 expression resulted in rapid cell cycle exit and reduced cell proliferation, suggesting that these cells are less likely to form tumors after transplantation. Our findings indicate a potential utility of this factor in efficient generation of a safe type of cells for therapeutic applications in Parkinson’s disease.