(+)4-Cholesten-3-one promotes differentiation of neural stem cells into dopaminergic neurons through TET1 and FoxA2. (14th September 2020)

• Record Type: Journal Article
• Authors: Ye, Sen; Zhong, Jun; Huang, Jiapei; Zhang, SaiXia; Li, Hui; Chen, DongFeng; Li, CaiXia
• Is Part Of: Neuroscience letters. Volume 735(2020)
• Publication Date: 2020-09-14
• Subjects: NSC neural stem cell -- TET1 ten-eleven translocation 1 -- FoxA2 fork-head box A2 -- PD Parkinson's disease -- TH tyrosine hydroxylase -- DA dopamine -- siRNA small interfering RNA -- h hours -- min minutes; Neural stem cell (NSC) -- (+)4-Cholesten-3-one -- Ten-eleven translocation 1 (TET1) -- Fork-head box A2 (FoxA2); Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2020.135239
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: (+)4-cholesten-3-one increase the tyrosine hydroxylase(TH). (+)4-cholesten-3-one increase the global DNA demethylation and the transcription factor fork-head box a2 (FoxA2). (+)4-cholesten-3-one increase the binding of TET1 and FoxA2. Binding of TET1 and FoxA2 is essential for NSC differentiation to dopaminergic neurons. (+)4-cholesten-3-one can induce NSC differentiation into dopaminergic neurons though TET1 and FoxA2. Abstract: In this paper, we report the results of treating cells with an effective small molecule, (+)4-cholesten-3-one (PubChem CID: 91477), which can promote neural stem cell(NSC) differentiation into dopaminergic neurons. This study used rat neural stem cells stimulated with two different concentrations (7.8 μM and 78 μM) of (+)4-cholesten-3-one. Cell phenotypic analysis showed that (+)4-cholesten-3-one induced NSC differentiation into dopaminergic neurons, and the level of tyrosine hydroxylase(TH), which is specific for dopaminergic cells, was significantly increased compared with that of the drug-free control group. Furthermore, in this study, we found that this effect may be related to the transcription factor fork-head box a2 (FoxA2) and ten-eleven translocation 1 (TET1). The expression of TET1 and FoxA2 was upregulated after treatment with (+)4-cholesten-3-one. To verify the relationship between (+)4-cholesten-3-one and these genes, we found that the binding rate of TET1 and FoxA2 increased after the application of (+)4-cholesten-3-one, as confirmed by a coimmunoprecipitation (Co-IP) assay. With a small interfering RNA (siRNA) experiment, we found that only when Tet1 and Foxa2 were not silenced was the mRNA level of Th increased after (+)4-cholesten-3-one treatment. Taken together, these data show that (+)4-cholesten-3-one can promote the differentiation of NSCs into dopaminergic neurons by upregulating the expression of TET1 and FoxA2 and by increasing their binding. Thus, (+)4-cholesten-3-one may help address the application of neural stem cell replacement therapy in neurodegenerative diseases.