Kir6.2 Deficiency Promotes Mesencephalic Neural Precursor Cell Differentiation via Regulating miR-133b/GDNF in a Parkinson’s Disease Mouse Model
The loss of dopaminergic (DA) neurons in the substantia nigra (SN) is a major feature in the pathology of Parkinson’s disease (PD). Using neural stem or progenitor cells (NSC/NPCs), the prospect of replacing the missing or damaged DA neurons is very attractive for PD therapy. However, little is known about the endogenous mechanisms and molecular pathways regulating the NSC/NPC proliferation and differentiation in the development of PD. Herein, using Kir6.2 knockout (Kir6.2−/−) mice, we observed that genetic deficiency of Kir6.2 exacerbated the loss of SN DA neurons relatively early in a chronic MPTP/probenecid (MPTP/p) injection course, but rescued the damage of neurons 7 days after the last MPTP/p injection. Meanwhile, we found that Kir6.2 knockout predominantly increased the differentiation of nuclear receptor-related 1 (Nurr1+) precursors to DA neurons, indicating that Kir6.2 deficiency could activate an endogenous self-repair process. Furthermore, we demonstrated in vivo and in vitro that lack of Kir6.2 promoted neuronal differentiation via inhibiting the downregulation of glia cell line-derived neurotrophic factor (GDNF), which negatively related to the level of microRNA-133b. Notably, we revealed that Gdnf is a target gene of miR-133b and transfection of miR-133b could attenuate the enhancement of neural precursor differentiation induced by Kir6.2 deficiency. Collectively, we clarify for the first time that Kir6.2/K-ATP channel functions as a novel endogenous negative regulator of NPC differentiation, and provide a promising neuroprotective target for PD therapeutics.
KeywordsKir6.2/K-ATP Adult neurogenesis Nurr1+ precursors Differentiation miR-133b Parkinson’s disease
The work reported herein was supported by the grants from the National Natural Science Foundation of China (No. 81630099, No. 81473196, No. 81773706, No. 81573403, and No. 81603083) and the key project of Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (No. 15KJA310002) and Natural Science Foundation of Jiangsu Province (BK20151559). Kir6.2 knockout mice were friendly donated by Professor Miki (Chiba University, Japan).
Compliance with Ethical Standards
All animal experiments were performed in accordance with the institutional guidelines for animal use and care, and the study protocol was approved by the ethical committee of Nanjing Medical University.
Conflict of Interest
The authors declare that they have no conflict of interest.
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