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tPA Regulates Neurite Outgrowth by Phosphorylation of LRP5/6 in Neural Progenitor Cells

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Abstract

Despite the important role of tissue plasminogen activator (tPA) as a neuromodulator in neurons, microglia, and astrocytes, its role in neural progenitor cell (NPC) development is not clear yet. We identified that tPA is highly expressed in NPCs compared with neurons. Inhibition of tPA activity or expression using tPA stop, PAI-1, or tPA siRNA inhibited neurite outgrowth from NPCs, while overexpression or addition of exogenous tPA increased neurite outgrowth. The expression of Wnt and β-catenin as well as phosphorylation of LRP5 and LRP6, which has been implicated in Wnt–β-catenin signaling, was rapidly increased after tPA treatment and was decreased by tPA siRNA transfection. Knockdown of β-catenin or LRP5/6 expression by siRNA prevented tPA-induced neurite extension. NPCs obtained from tPA KO mice showed impaired neurite outgrowth compared with WT NPCs. In ischemic rat brains, axon density was higher in the brains transplanted with WT NPCs than in those with tPA KO NPCs, suggesting increased axonal sprouting by NPC-derived tPA. tPA-mediated regulation of neuronal maturation in NPCs may play an important role during development and in regenerative conditions.

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Acknowledgments

This work was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (No. A120029), and by the Mid-career Researcher Program Project No. 2011–0014258 through the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (Shin, C.Y.).

Conflict of Interest

The authors declare no conflict of interest or competing commercial interests.

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Authors and Affiliations

  1. Department of Neuroscience, School of Medicine and Center for Neuroscience Research, IBST, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul, 143-701, Republic of Korea

    Sung Hoon Lee, Hyun Myung Ko, Kyoung Ja Kwon, Jongmin Lee, Seol-Heui Han & Chan Young Shin

  2. Department of Stem Cell Biology, School of Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul, 143-701, Republic of Korea

    Dong Wook Han

  3. Institute of Functional Genomics, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul, 143-701, Republic of Korea

    Dong Wook Han & Chan Young Shin

  4. College of Pharmacy and Uimyung Research Institute for Neuroscience, Sahmyook University, Seoul, Republic of Korea

    Jae Hoon Cheong

  5. Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, 1 Hoeki-dong, Dongdaemoon-Gu, Seoul, 130-701, Republic of Korea

    Jong Hoon Ryu

  6. Department of Pharmacology, School of Medicine, Konkuk University, 1 Hwayang-Dong, Gwangjin-Gu, Seoul, Republic of Korea

    Chan Young Shin

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  1. Sung Hoon Lee
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Correspondence to Jong Hoon Ryu or Chan Young Shin.

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Sung Hoon Lee and Hyun Myung Ko contributed equally to this work.

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Lee, S.H., Ko, H.M., Kwon, K.J. et al. tPA Regulates Neurite Outgrowth by Phosphorylation of LRP5/6 in Neural Progenitor Cells. Mol Neurobiol 49, 199–215 (2014). https://doi.org/10.1007/s12035-013-8511-x

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