Abstract
During the development of the central nervous system, the proliferation of neural progenitors and differentiation of neurons and glia are tightly regulated by different transcription factors and signaling cascades, such as the Wnt and Shh pathways. This process takes place in cooperation with several microRNAs, some of which evolutionarily conserved in vertebrates, from teleosts to mammals. We focused our attention on miR-7, as its role in the regulation of cell signaling during neural development is still unclear. Specifically, we used human stem cell cultures and whole zebrafish embryos to study, in vitro and in vivo, the role of miR-7 in the development of dopaminergic (DA) neurons, a cell type primarily affected in Parkinson’s disease. We demonstrated that the zebrafish homologue of miR-7 (miR-7a) is expressed in the forebrain during the development of DA neurons. Moreover, we identified 143 target genes downregulated by miR-7, including the neural fate markers TCF4 and TCF12, as well as the Wnt pathway effector TCF7L2. We then demonstrated that miR-7 negatively regulates the proliferation of DA-progenitors by inhibiting Wnt/β-catenin signaling in zebrafish embryos. In parallel, miR-7 positively regulates Shh signaling, thus controlling the balance between oligodendroglial and DA neuronal cell fates. In summary, this study identifies a new molecular cross-talk between Wnt and Shh signaling pathways during the development of DA-neurons. Being mediated by a microRNA, this mechanism represents a promising target in cell differentiation therapies for Parkinson’s disease.
Highlights
Parkinson’s disease (PD) is one of the most common conditions affecting the elderly population.It causes disabling motor abnormalities that manifest as tremor, slow movements, rigidity, and poor balance
In a microarray screen for miRNAs differentially expressed upon differentiation of a human neuroblastoma cell line (SH-SY5Y), we identified microRNA 7 (miR-7) as one of the most upregulated miRNAs during the process of neuronal differentiation; this upregulation was validated using Northern blot analysis [36]
To identify the targets of miR-7 in neuronal progenitor cells, we performed a microarray analysis of H9 ES-derived human neural progenitor cells transfected with miR-7 duplex (7DP), compared with a control duplex (NCDP)
Summary
Parkinson’s disease (PD) is one of the most common conditions affecting the elderly population. Wnt signaling has been implicated in the formation of mDA neurons and supporting glia cells, such as myelinating oligodendrocytes, regulated by the transcription factor Olig2 [9,10,11,12,13]. MiR-133b, for example, is a midbrain-specific miRNA found to be deficient in PD midbrain tissue and is involved in the maturation of DA neurons through a negative regulatory feedback loop involving the transcription factor PITX3 [17] Another miRNA, miR-7 ( known as miR-7a), has been shown to spatially control the rate of DA neuron production in the forebrain, by post-transcriptionally regulating the DA determinant Pax, a known Wnt-target factor [18]. Through over-expression and knock-down experiments in human cells and zebrafish carrying Wnt pathway reporters, we demonstrate here that miR-7 negatively regulates the Wnt/β-catenin response, playing a key role in the balance between oligodendroglial and DA neuronal cell fates
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