miR-7 Controls the Dopaminergic/Oligodendroglial Fate through Wnt/β-catenin Signaling Regulation

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.

circHIPK3 regulates proliferation and differentiation of myoblast through the miR‐7/TCF12 pathway

“…In this study, we identified TCF12 as a target of miR‐7 in C2C12 cells. This is consistent with the results of Adusumilli, who found that miR‐7 targeted TCF12 in human neural progenitor cells involved in neural development (Adusumilli et al, 2020). The protein encoded by TCF12 (also known as HEB ) is a member of the basic helix‐loop‐helix (bHLH) E‐protein family, which is expressed in many tissues, such as skeletal muscle, thymus, B‐ and T‐cells (Massari & Murre, 2000).…”

Kappa opioid receptor controls neural stem cell differentiation via a miR-7a/Pax6 dependent pathway

“…Since miR‐7a has a variety of targets other than Pax6 , especially in the central nervous system, it might have other effects beyond the regulation of Pax6 and neurogenesis. For example, miR‐7a controls the balance between oligodendroglial and dopaminergic neuronal cell fates by inhibiting Wnt signaling and facilitating Shh signaling, 39 which might account for the depression‐like effects of OPRK1 agonists. Besides, the neural protective effect of miR‐7a was discovered by a series of studies, as it was able to inhibit neuronal apoptosis and oxidative stress in oxygen‐glucose deprivation (OGD) model, 40,41 and to ameliorate ischemic damage 42 .…”

Chemical and Biological Molecules Involved in Differentiation, Maturation, and Survival of Dopaminergic Neurons in Health and Parkinson’s Disease: Physiological Aspects and Clinical Implications

“…miR-125b and miR-181 appear to specifically promote the differentiation of hESCs towards the DA fate, because the percentage of TH + cells is enhanced by the ectopic expression of these two miRNAs [64]. Conversely, in vitro studies on hESCs evidenced that the overexpression of miR-7a led to a decrease of TH + neurons by altering the balance between Wnt and Shh signaling and consequently promoting the switch to glial cell populations; coherently, its knockdown increases the number of DA neurons [65]. Similarly, the hyperexpression of miRNA-124 led to a reduction of TH + neurons.…”