Dose-Dependent and Subset-Specific Regulation of Midbrain Dopaminergic Neuron Differentiation by LEF1-Mediated WNT1/b-Catenin Signaling.

Autor:	Nouri P; Laboratory of Applied Genetics and Stem Cell Biology, Department Hamm 2, Hamm-Lippstadt University of Applied Sciences, Hamm, Germany., Götz S; Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany., Rauser B; Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany., Irmler M; Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany., Peng C; Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.; Advanced Institute of Translational Medicine, The First Rehabilitation Hospital of Shanghai, Tongji University School of Medicine, Tongji University, Shanghai, China., Trümbach D; Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany., Kempny C; Laboratory of Applied Genetics and Stem Cell Biology, Department Hamm 2, Hamm-Lippstadt University of Applied Sciences, Hamm, Germany., Lechermeier CG; Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany., Bryniok A; Laboratory of Applied Genetics and Stem Cell Biology, Department Hamm 2, Hamm-Lippstadt University of Applied Sciences, Hamm, Germany., Dlugos A; Laboratory of Applied Genetics and Stem Cell Biology, Department Hamm 2, Hamm-Lippstadt University of Applied Sciences, Hamm, Germany., Euchner E; Laboratory of Applied Genetics and Stem Cell Biology, Department Hamm 2, Hamm-Lippstadt University of Applied Sciences, Hamm, Germany., Beckers J; Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.; Chair of Experimental Genetics, Technical University of Munich, Munich, Germany.; German Center for Diabetes Research, Neuherberg, Germany., Brodski C; Department of Physiology and Cell Biology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel., Klümper C; Laboratory of Applied Genetics and Stem Cell Biology, Department Hamm 2, Hamm-Lippstadt University of Applied Sciences, Hamm, Germany., Wurst W; Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.; Chair of Developmental Genetics, Helmholtz Zentrum München, Technical University of Munich/Helmholtz Zentrum München, Neuherberg, Germany.; German Center for Neurodegenerative Diseases, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Prakash N; Laboratory of Applied Genetics and Stem Cell Biology, Department Hamm 2, Hamm-Lippstadt University of Applied Sciences, Hamm, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2020 Oct 26; Vol. 8, pp. 587778. Date of Electronic Publication: 2020 Oct 26 (Print Publication: 2020).
DOI:	10.3389/fcell.2020.587778
Abstrakt:	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. (Copyright © 2020 Nouri, Götz, Rauser, Irmler, Peng, Trümbach, Kempny, Lechermeier, Bryniok, Dlugos, Euchner, Beckers, Brodski, Klümper, Wurst and Prakash.)
Databáze:	MEDLINE
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