Abstract
Bcl-2 is overexpressed in the nervous system during neural development and plays an important role in modulating cell survival. In addition to its anti-apoptotic function, it has been suggested previously that Bcl-2 might act as a mediator of neuronal differentiation. However, the mechanism by which Bcl-2 might influence neurogenesis is not sufficiently understood. In this study, we aimed to determine the non-apoptotic functions of Bcl-2 during neuronal differentiation. First, we used microarrays to analyze the whole-genome expression patterns of rat neural stem cells overexpressing Bcl-2 and found that Bcl-2 overexpression induced the expression of various neurogenic genes. Moreover, Bcl-2 overexpression increased the neurite length as well as expression of Bmp4, Tbx3, and proneural basic helix–loop–helix genes, such as NeuroD1, NeuroD2, and Mash1, in H19-7 rat hippocampal precursor cells. To determine the hierarchy of these molecules, we selectively depleted Bmp4, Tbx3, and NeuroD1 in Bcl-2-overexpressing cells. Bmp4 depletion suppressed the upregulation of Tbx3 and NeuroD1 as well as neurite outgrowth, which was induced by Bcl-2 overexpression. Although Tbx3 knockdown repressed Bcl-2-mediated neurite elaboration and downregulated NeuroD1 expression, it did not affect Bcl-2-induced Bmp4 expression. While the depletion of NeuroD1 had no effect on the expression of Bcl-2, Bmp4, or Tbx3, Bcl-2-mediated neurite outgrowth was suppressed. Taken together, these results demonstrate that Bcl-2 regulates neurite outgrowth through the Bmp4/Tbx3/NeuroD1 cascade in H19-7 cells, indicating that Bcl-2 may have a direct role in neuronal development in addition to its well-known anti-apoptotic function in response to environmental insults.
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Abbreviations
- NPCs:
-
Neural precursor cells
- bHLH:
-
Basic helix–loop–helix
- CNS:
-
Central nervous system
- bFGF:
-
Basic fibroblast growth factor
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Acknowledgements
This work was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean government (MSIP) (NRF-2016R1A2B4015358) and partly supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2013R1A1A2061420). In addition, this research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI19C0611), and supported by the research fund of Hanyang University (HY-2019).
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YY Lee conceptualized and designed of the study, collected and assembled the data, analyzed and interpreted the results, and wrote the manuscript. H-J Choi conceptualized and designed the study and provided financial support. SY Lee analyzed the microarray data and performed some of the experiments. S-Y Park analyzed and interpreted the results. M-J Kang conducted some of the experiments. J Han analyzed the microarray data. J-S Han conceptualized and designed the study, analyzed and interpreted the data, wrote the manuscript, and provided financial support. All authors read and approved the final manuscript.
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Lee, Y.Y., Choi, Hj., Lee, S.Y. et al. Bcl-2 Overexpression Induces Neurite Outgrowth via the Bmp4/Tbx3/NeuroD1 Cascade in H19-7 Cells. Cell Mol Neurobiol 40, 153–166 (2020). https://doi.org/10.1007/s10571-019-00732-1
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DOI: https://doi.org/10.1007/s10571-019-00732-1