%A Nouri,Parivash %A Götz,Sebastian %A Rauser,Benedict %A Irmler,Martin %A Peng,Changgeng %A Trümbach,Dietrich %A Kempny,Christian %A Lechermeier,Carina G. %A Bryniok,Agnes %A Dlugos,Andrea %A Euchner,Ellen %A Beckers,Johannes %A Brodski,Claude %A Klümper,Claudia %A Wurst,Wolfgang %A Prakash,Nilima %D 2020 %J Frontiers in Cell and Developmental Biology %C %F %G English %K Dopamine,Nerve cell,Parkinson's disease,Regenerative therapy,Mouse %Q %R 10.3389/fcell.2020.587778 %W %L %M %P %7 %8 2020-October-26 %9 Original Research %# %! WNT/b-Catenin dose-dependent mDA neuron generation %* %< %T Dose-Dependent and Subset-Specific Regulation of Midbrain Dopaminergic Neuron Differentiation by LEF1-Mediated WNT1/b-Catenin Signaling %U https://www.frontiersin.org/articles/10.3389/fcell.2020.587778 %V 8 %0 JOURNAL ARTICLE %@ 2296-634X %X The mesodiencephalic dopaminergic (mdDA) neurons, including the nigrostriatal subset that preferentially degenerates in Parkinson’s Disease (PD), strongly depend on an accurately balanced Wingless-type MMTV integration site family member 1 (WNT1)/beta-catenin signaling pathway during their development. Loss of this pathway abolishes the generation of these neurons, whereas excessive WNT1/b-catenin signaling prevents their correct differentiation. The identity of the cells responding to this pathway in the developing mammalian ventral midbrain (VM) as well as the precise progression of WNT/b-catenin action in these cells are still unknown. We show that strong WNT/b-catenin signaling inhibits the differentiation of WNT/b-catenin-responding mdDA progenitors into PITX3+ and TH+ mdDA neurons by repressing the Pitx3 gene in mice. This effect is mediated by RSPO2, a WNT/b-catenin agonist, and lymphoid enhancer binding factor 1 (LEF1), an essential nuclear effector of the WNT/b-catenin pathway, via conserved LEF1/T-cell factor binding sites in the Pitx3 promoter. LEF1 expression is restricted to a caudolateral mdDA progenitor subset that preferentially responds to WNT/b-catenin signaling and gives rise to a fraction of all mdDA neurons. Our data indicate that an attenuation of WNT/b-catenin signaling in mdDA progenitors is essential for their correct differentiation into specific mdDA neuron subsets. This is an important consideration for stem cell-based regenerative therapies and in vitro models of neuropsychiatric diseases.