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ATP and spontaneous calcium oscillations control neural stem cell fate determination in Huntington’s disease: a novel approach for cell clock research

Abstract

Calcium, the most versatile second messenger, regulates essential biology including crucial cellular events in embryogenesis. We investigated impacts of calcium channels and purinoceptors on neuronal differentiation of normal mouse embryonic stem cells (ESCs), with outcomes being compared to those of in vitro models of Huntington’s disease (HD). Intracellular calcium oscillations tracked via real-time fluorescence and luminescence microscopy revealed a significant correlation between calcium transient activity and rhythmic proneuronal transcription factor expression in ESCs stably expressing ASCL-1 or neurogenin-2 promoters fused to luciferase reporter genes. We uncovered that pharmacological manipulation of L-type voltage-gated calcium channels (VGCCs) and purinoceptors induced a two-step process of neuronal differentiation. Specifically, L-type calcium channel-mediated augmentation of spike-like calcium oscillations first promoted stable expression of ASCL-1 in differentiating ESCs, which following P2Y2 purinoceptor activation matured into GABAergic neurons. By contrast, there was neither spike-like calcium oscillations nor responsive P2Y2 receptors in HD-modeling stem cells in vitro. The data shed new light on mechanisms underlying neurogenesis of inhibitory neurons. Moreover, our approach may be tailored to identify pathogenic triggers of other developmental neurological disorders for devising targeted therapies.

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Fig. 1: Roles of extracellular nucleotide receptors and voltage-gated calcium channels in RA-induced neural differentiation of ESCs.
Fig. 2: Effects of VGCCs and P2Y2 and P2X7 receptor-induced signaling on NPC differentiation.
Fig. 3: Effects of P2X7 and P2Y2 receptors on spontaneous calcium oscillations and proneural ASCL-1 and Ngn2 bHLH transcription factor expression during neurogenesis, as determined by time-lapse recording.
Fig. 4: human NPCs from HD-patient iPSCs do not show spike-like [Ca2+]i oscillations.
Fig. 5: Influence of mHtt overexpression on ESC neuronal differentiation and P2Y2 receptor activity.

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Acknowledgements

We thank Adriana Yamaguti Matsukuma, Denise Yamamoto, Wilton José da Rocha Lima and Zilda Mendonça Izzo for technical assistance, Prof. Deborah Schechtman, Department of Biochemistry, Institute of Chemistry, University of São Paulo, for donating the E14Tg2A cell line and Prof. Dr. Soraya Smaili, Federal University of São Paulo for donating the Q23 and Q74 plasmids. This work was supported by the Brazilian funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grant number 467465/2014–2), INCT-REGENERA (National Institute of Science and Technology) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (grant numbers 2012/50880–4, 2015/13345–1, 2010/50554–4 and 2018/07366–4). Japanese grants included a Grant-in-Aid for Scientific Research on Innovative Areas (Ministry of Education, Culture, Sports, Science, and Technology 16H06480) (RK), a Scientific Research (A) grant (Japan Society for Promotion of Science [JSPS] 24240049) (RK), a Young Scientists (A) grant (JSPS 24680035) (II), and a Takeda Foundation grant (RK). US grants that facilitated the project were W81XWH-15-1-0621 (DoD), 1-I01-RX000308-01A1 (VA), and funds from The Gordon Project to Cure Clinical Paralysis and Cele H. and William B. Rubin Family Fund, Incorporated (YDT). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Henning Ulrich.

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Glaser, T., Shimojo, H., Ribeiro, D.E. et al. ATP and spontaneous calcium oscillations control neural stem cell fate determination in Huntington’s disease: a novel approach for cell clock research. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0717-5

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