Journal Article

DZNE-2021-00120

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dose-Dependent and Subset-Specific Regulation of Midbrain Dopaminergic Neuron Differentiation by LEF1-Mediated WNT1/b-Catenin Signaling.

Nouri, P. ; Götz, S. ; Rauser, B. ; Irmler, M. ; Peng, C. ; Trümbach, D. ; Kempny, C. ; Lechermeier, C. G. ; Bryniok, A. ; Dlugos, A. ; Euchner, E. ; Beckers, J. ; Brodski, C. ; Klümper, C. ; Wurst, W.DZNE* ; Prakash, N. (Corresponding author)

2020
Frontiers Media Lausanne

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Please use a persistent id in citations: doi:10.3389/fcell.2020.587778

Abstract: 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.

Keyword(s): Parkinson’s disease ; dopamine ; mouse ; nerve cell ; regenerative therapy

Note: ISSN 2296-634X not unique: **3 hits**.

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Contributing Institute(s):

1. Ext HZM (Ext HZM)
2. Genome Engineering (AG Wurst)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2020

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Database coverage:
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