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.
Highlights
The generation of dopamine-synthesizing neurons in the mouse midbrain and from human and murine pluripotent stem cells (PSCs) crucially relies on signal transduction by the Wingless-type MMTV integration site family member 1 (WNT1)/beta-catenin (b-catenin, Ctnnb1) pathway (Joksimovic and Awatramani, 2014; Brodski et al, 2019)
The microarray-based transcriptome profiling of the WNT/bcatenin-responding mesodiencephalic dopaminergic (mdDA) domain in the BAT-gal ventral midbrain (VM) and subsequent expression pattern analysis of candidate genes revealed that the postmitotic mdDA precursor/neuron marker Pitx3 and two activating components of the WNT/b-catenin pathway, Rspo2 and Lef1, are expressed in mutually exclusive domains in the mouse VM
R-spondin 2 (RSPO2) is a potent activator or enhancer of WNT/b-catenin signaling that inhibited the differentiation of E11.5 VM progenitors into maturing PITX3+/TH+ mdDA neurons in a dose-dependent manner and without affecting their proliferation [this study, (Kim et al, 2008)]
Summary
The generation of dopamine-synthesizing (dopaminergic, DA) neurons in the mouse midbrain and from human and murine pluripotent stem cells (PSCs) crucially relies on signal transduction by the Wingless-type MMTV integration site family member 1 (WNT1)/beta-catenin (b-catenin, Ctnnb1) pathway (Joksimovic and Awatramani, 2014; Brodski et al, 2019). These neurons comprise the Substantia nigra pars compacta (SNc) subset that preferentially degenerates in PD, and the ventral tegmental area (VTA) subpopulation implicated in a variety of human neuropsychiatric disorders, including schizophrenia and addiction (Schultz, 2007; Lees et al, 2009). The participation of WNT1/b-catenin signaling in the subsequent differentiation of these mdDA precursors into mature neurons expressing the full complement of mdDA-specific markers, such as the TFs PITX3 and NURR1 (NR4A2), tyrosine hydroxylase (TH, the rate-limiting enzyme for DA synthesis), dopamine transporter (DAT, SLC6A3), and other proteins implicated in DA metabolism, storage and neurotransmission, remains unclear (Arenas, 2014; Wurst and Prakash, 2014)
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