TY  - JOUR
AU  - Nouri, Parivash
AU  - Götz, Sebastian
AU  - Rauser, Benedict
AU  - Irmler, Martin
AU  - Peng, Changgeng
AU  - Trümbach, Dietrich
AU  - Kempny, Christian
AU  - Lechermeier, Carina G
AU  - Bryniok, Agnes
AU  - Dlugos, Andrea
AU  - Euchner, Ellen
AU  - Beckers, Johannes
AU  - Brodski, Claude
AU  - Klümper, Claudia
AU  - Wurst, Wolfgang
AU  - Prakash, Nilima
TI  - Dose-Dependent and Subset-Specific Regulation of Midbrain Dopaminergic Neuron Differentiation by LEF1-Mediated WNT1/b-Catenin Signaling.
JO  - Frontiers in cell and developmental biology
VL  - 8
SN  - 2296-634X
CY  - Lausanne
PB  - Frontiers Media
M1  - DZNE-2021-00120
SP  - 587778
PY  - 2020
N1  - ISSN 2296-634X not unique: **3 hits**.
AB  - 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.
KW  - Parkinson’s disease (Other)
KW  - dopamine (Other)
KW  - mouse (Other)
KW  - nerve cell (Other)
KW  - regenerative therapy (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:33195246
C2  - pmc:PMC7649324
DO  - DOI:10.3389/fcell.2020.587778
UR  - https://pub.dzne.de/record/154266
ER  -