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000154266 041__ $$aEnglish
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000154266 1001_ $$aNouri, Parivash$$b0
000154266 245__ $$aDose-Dependent and Subset-Specific Regulation of Midbrain Dopaminergic Neuron Differentiation by LEF1-Mediated WNT1/b-Catenin Signaling.
000154266 260__ $$aLausanne$$bFrontiers Media$$c2020
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000154266 520__ $$aThe 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.
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000154266 650_7 $$2Other$$aParkinson’s disease
000154266 650_7 $$2Other$$adopamine
000154266 650_7 $$2Other$$amouse
000154266 650_7 $$2Other$$anerve cell
000154266 650_7 $$2Other$$aregenerative therapy
000154266 7001_ $$aGötz, Sebastian$$b1
000154266 7001_ $$aRauser, Benedict$$b2
000154266 7001_ $$aIrmler, Martin$$b3
000154266 7001_ $$aPeng, Changgeng$$b4
000154266 7001_ $$0P:(DE-HGF)0$$aTrümbach, Dietrich$$b5
000154266 7001_ $$aKempny, Christian$$b6
000154266 7001_ $$aLechermeier, Carina G$$b7
000154266 7001_ $$aBryniok, Agnes$$b8
000154266 7001_ $$aDlugos, Andrea$$b9
000154266 7001_ $$aEuchner, Ellen$$b10
000154266 7001_ $$aBeckers, Johannes$$b11
000154266 7001_ $$aBrodski, Claude$$b12
000154266 7001_ $$aKlümper, Claudia$$b13
000154266 7001_ $$0P:(DE-2719)2000028$$aWurst, Wolfgang$$b14$$udzne
000154266 7001_ $$0P:(DE-HGF)0$$aPrakash, Nilima$$b15$$eCorresponding author
000154266 773__ $$0PERI:(DE-600)2737824-X$$a10.3389/fcell.2020.587778$$gVol. 8, p. 587778$$p587778$$tFrontiers in cell and developmental biology$$v8$$x2296-634X$$y2020
000154266 8564_ $$uhttps://www.frontiersin.org/articles/10.3389/fcell.2020.587778/full
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