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GDNF Promotes Astrocyte Abnormal Proliferation and Migration Through the GFRα1/RET/MAPK/pCREB/LOXL2 Signaling Axis

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Abstract

Glial cell-line derived neurotrophic factor (GDNF) is a powerful astroglioma (AG) proliferation and migration factor that is highly expressed in AG cells derived from astrocytes. However, it is still unclear whether high levels of GDNF promote AG occurrence or if they are secondary to AG formation. We previously reported that high concentrations of GDNF (200 and 500 ng/mL) can inhibit DNA damage-induced rat primary astrocytes (RA) apoptosis, suggesting that high concentrations of GDNF may be involved in the malignant transformation of astrocytes to AG cells. Here we show that 200 ng/mL GDNF significantly increased the proliferation and migration ability of RA cells and human primary astrocytes (HA). This treatment also induced RA cells to highly express Pgf, Itgb2, Ibsp, Loxl2, Lif, Cxcl10, Serpine1, and other genes that enhance AG proliferation and migration. LOXL2 is an important AG occurrence and development promotion factor and was highly expressed in AG tissues and cells. High concentrations of GDNF promote LOXL2 expression and secretion in RA cells through GDNF family receptor alpha-1(GFRα1)/rearranged during transfection proto-oncogene (RET)/mitogen-activated protein kinase (MAPK)/phosphorylated cyclic AMP response element binding protein (pCREB) signaling. GDNF-induced LOXL2 significantly promotes RA and HA cell proliferation and migration, and increases the expression of Ccl2, Gbp5, MMP11, TNN, and other genes that regulate the extracellular microenvironment in RA cells. Our results demonstrate that high concentrations of GDNF activate LOXL2 expression and secretion via the GFRα1/RET/MAPK/pCREB signal axis, which leads to remodeling of the astrocyte extracellular microenvironment through molecules such as Ccl2, Gbp5, MMP11, TNN. This ultimately results in abnormal astrocyte proliferation and migration. Collectively, these findings suggest that high GDNF concentrations may promote the malignant transformation of astrocytes to AG cells.

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Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material; further inquiries can be directed to the corresponding author.

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Acknowledgements

We thank Zhonglin Li (the affiliated hospitals of Xuzhou Medical University, China) for providing clinical human glioma samples and Piniel Alphayo Kambey for revising this manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (nos. 81602464 to B. L. Zhang, and 81772688 to D. S. Gao), Six Talent Peaks in Jiangsu Province Jiangsu (SWYY-088 to B. L. Zhang), the 333 Project of Jiangsu Province (to B. L. Zhang), Qing Lan Project in Jiangsu Province (2017 to B. L. Zhang), Xuzhou Science and Technology Plan Project (KC20145 to B. L. Zhang), and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD to D. S. Gao). Special thanks to the staff of the Public Experimental Research Center of Xuzhou Medical University. We acknowledge the use of their laboratories to complete some of our research works.

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  1. Miaomiao Wang and Xiao Han contributed equally and share first authorship.

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  1. Department of Neurobiology and Anatomy, Xuzhou Key Laboratory of Neurobiology, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China

    Miaomiao Wang, Xiao Han, Wei Zha, Xiaoyu Wang, Liyun Liu, Zimu Li, Yefeng Shi, Xugang Kan, Gui Wang, Dianshuai Gao & Baole Zhang

  2. Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Xiao Han

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Contributions

BLZ and DSG designed the study and oversaw the project. MMW, XH, WZ, XYW, LYL, ZML, YFS, XGK, GW, and BLZ performed the experiment and collected the data. MMW, XH, WZ, XYW, LYL, GW, and BLZ performed data analyses and produced the manuscript and the figures. All authors reviewed the manuscript and approved the submitted version.

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Correspondence to Dianshuai Gao or Baole Zhang.

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All experiments were carried out in compliance with the Provisions and General Recommendations of the Chinese Experimental Animal Administration Regulations, as well as institutional consent from the Xuzhou Medical University Animal Ethics Committee. Human GBM and NB tissue samples were obtained from the surgical specimen archives of Xuzhou Medical University’s affiliated hospitals with written informed consent from the patients.

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Wang, M., Han, X., Zha, W. et al. GDNF Promotes Astrocyte Abnormal Proliferation and Migration Through the GFRα1/RET/MAPK/pCREB/LOXL2 Signaling Axis. Mol Neurobiol 59, 6321–6340 (2022). https://doi.org/10.1007/s12035-022-02978-1

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