%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.