Abstract
The canonical Wnt signaling pathway is critical for the development of midbrain dopaminergic (DA) neurons, and recent studies have suggested that disruption of this signaling cascade may underlie the pathogenesis of Parkinson’s disease (PD). However, the exact role of the canonical Wnt signaling pathway, including low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) and β-catenin components, in a mouse model of PD remains unclear. In the present study, the tyrosine hydroxylase (TH)-Cre transgenic mouse line was used to generate mice with the specific knockout of LRP5, LRP6 or β-catenin in DA neurons. Following inactivation of LRP5, LRP6 or β-catenin, TH-immunohistochemical staining was performed. The results indicated that β-catenin is required for the development or maintenance of these neurons; however, LRP5 and LRP6 were found to be dispensable. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, the depletion of LRP5, LRP6 or β-catenin was found to be protective for the midbrain DA neurons to a certain extent. These in vivo results provide a novel perspective for the function of the canonical Wnt signaling pathway in a mouse model of PD.
Highlights
The canonical Wnt signaling pathway is an ancient and conserved signaling cascade, which regulates cell proliferation, fate and behavior in contexts ranging from embryonic development to disease [1]
In wild‐type and LRP5 CKO mice treated with saline, no significant difference in the number of DA neurons in the SNc was observed (Fig. 1A, B and I), and the density of tyrosine hydroxylase (TH)‐ir axonal terminals in the striatum was comparable between the two genotypes (Fig. 1E, F and J)
In the MPTP‐treated LRP5 CKO mice, the TH‐ir neuronal number was decreased to ~73.9% of that in LRP5 CKO mice treated with saline (Fig. 1B, D and I)
Summary
The canonical Wnt signaling pathway is an ancient and conserved signaling cascade, which regulates cell proliferation, fate and behavior in contexts ranging from embryonic development to disease [1]. Wnt ligands bind to a receptor complex composed of Frizzled (Fzd) and low‐density lipoprotein receptor‐related protein 5 or 6 (LRP5/6) [2,3,4,5]. This complex leads to the accumulation of cytoplasmic β‐catenin, which translocates into the nucleus and activates the target genes by binding to members of the TCF/LEF transcription factor family [6]. The canonical Wnt signaling has a critical role in the development of the ventral mesencephalic dopaminergic (DA) neurons, whose selective loss in the substantia nigra (SNc) results in Parkinson's disease (PD) [8,9]. Wnt/β‐catenin signaling is involved in certain PD animal models induced by DA neuron‐specific toxins, including 6‐hydroxydopamine (6‐OHDA) [16] and 1‐methyl‐4‐phenyl‐1,2,3,6 tetrahydropyridine (MPTP) [17]
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