Dickkopf 3 Promotes the Differentiation of Substantia Nigra Dopaminergic Neurons In Vivo and from Pluripotent Stem Cells In Vitro

WNT1/beta-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons including the Substantia nigra pars compacta (SNc) subpopulation, whose degeneration is a hallmark of Parkinsons Disease (PD). However, the precise functions of WNT/beta-catenin signaling in this context remain unknown. Using mutant mice, primary ventral midbrain (VM) cells and pluripotent stem cells (mouse embryonic stem cells and induced pluripotent stem cells), we show that Dickkopf 3 (DKK3), a secreted glycoprotein that modulates WNT/beta-catenin signaling, is specifically required for the correct differentiation of a rostrolateral mdDA precursor subset into SNc DA neurons.

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Fukusumi Y, Meier F, Götz S, Matheus F, Irmler M, Beckervordersandforth R, Faus-Kessler T, Minina E, Rauser B, Zhang J, Arenas E, Andersson E, Niehrs C, Beckers J, Simeone A, Wurst W, Prakash N