%0 Journal Article
%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
%T Dose-Dependent and Subset-Specific Regulation of Midbrain Dopaminergic Neuron Differentiation by LEF1-Mediated WNT1/b-Catenin Signaling.
%J Frontiers in cell and developmental biology
%V 8
%@ 2296-634X
%C Lausanne
%I Frontiers Media
%M DZNE-2021-00120
%P 587778
%D 2020
%Z ISSN 2296-634X not unique: **3 hits**.
%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.
%K Parkinson’s disease (Other)
%K dopamine (Other)
%K mouse (Other)
%K nerve cell (Other)
%K regenerative therapy (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:33195246
%2 pmc:PMC7649324
%R 10.3389/fcell.2020.587778
%U https://pub.dzne.de/record/154266