Dose-dependent and subset-specific regulation of midbrain dopaminergic neuron differentiation by LEF1-mediated WNT1/b-Catenin signaling

ABSTRACT: The development of the mesodiencephalic dopaminergic (mdDA) neurons strongly depends on the WNT1/b-catenin signaling pathway. These neurons include the Substantia nigra pars compacta (SNc) subset that preferentially degenerates in Parkinson’s Disease (PD), and the ventral tegmental area (VTA) subpopulation implicated in a variety of neuropsychiatric disorders. The identity of the cells responding to this signaling pathway in the developing mammalian ventral midbrain (VM) and the precise mechanism of WNT/b-catenin action in these cells, however, are still unknown. Moreover, this signaling pathway has to be accurately balanced during mdDA neuron development: whereas low levels or absence of WNT1/b-catenin signaling abolish their correct specification, constitutive activation of this signaling pathway prevents their proper differentiation in the mouse. We show that the WNT/b-catenin-responsive cells constitute only a fraction of all mdDA progenitors, precursors and neurons in the murine VM. These WNT/b-catenin-responsive cells are mostly located in the Wnt1+, Rspo2+ and Lef1+ lateral floor plate of the medial and caudal midbrain, giving preferentially rise to caudomedial (VTA) mdDA neurons. Strong WNT/b-catenin signaling mediated by RSPO2, a WNT/b-catenin agonist, and LEF1, a nuclear effector of this pathway, inhibits the differentiation of WNT/b-catenin-responsive mdDA progenitors into mature mdDA neurons by repressing the murine Pitx3 gene via conserved LEF1/TCF binding sites in its promoter. 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, thus providing a new means for stem cell-based regenerative therapies of PD and in vitro models of neuropsychiatric diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE99618 | GEO | 2020/09/02

REPOSITORIES: GEO