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nNOS Translocates into the Nucleus and Interacts with Sox2 to Protect Neurons Against Early Excitotoxicity via Promotion of Shh Transcription

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Abstract

Cerebral ischemic stroke is a major public health problem leading to high mortality rates and disability in adults. The NMDA receptor (NMDAR)/neuronal nitric oxide synthase (nNOS)/NO-dependent excitotoxicity has been recognized to play an important role in cerebral ischemic stroke pathogenesis. Accumulating evidence suggests that the biological function of nNOS is associated with its ability to couple proteins and its subcellular localization. Previously, we and others determined that nNOS could translocate into the nucleus in cultured astrocytes, but the underlying mechanisms and biological significance remained unclear. In the present study, we identified a specific interaction between nNOS and Sox2 (SRY (sex determining region Y)-box 2), a member of the Sox family of transcription factors, both in vivo and in vitro. Our studies showed that nNOS is transported into the nucleus and interacted with Sox2 to form a nNOS-Sox2 complex in neurons at the early stage following glutamate stimulation. Mechanistically, via activating the transcription of Shh (Sonic hedgehog), the downstream target of Sox2, this nNOS-Sox2 complex exerted a neuroprotective function against glutamate-induced excitotoxicity. Utilizing the MCAO focal ischemia model on rats, we further verified that the ‘nNOS-Sox2-Shh’ axis was involved in the ischemic neuronal injury. Taken together, our studies revealed that the ‘nNOS-Sox2-Shh’ axis functions as a novel feedback compensatory mechanism to protect neurons against the early excitotoxicity and ischemic injury.

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Acknowledgments

This work was supported by National Basic Research Program of China (973 Program, 2012CB822104, 2011CB910604); the National Nature Science Foundation of China (31440037, 31270802, 81471256, 81272789, 31500647); the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (15KJA310003); the Natural Science Foundation of Jiangsu Province (BK20150408); A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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    Authors and Affiliations

    1. Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong, 226001, Jiangsu Province, People’s Republic of China

      Dongmei Zhang, Hongmei Wang, Hanzhang Liu, Tao Tao, Ning Wang & Aiguo Shen

    2. Department of Pathogen Biology, Medical College, Nantong University, Nantong, 226001, Jiangsu Province, People’s Republic of China

      Dongmei Zhang

    3. Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, People’s Republic of China

      Hongmei Wang

    4. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, Jiangsu Province, People’s Republic of China

      Aiguo Shen

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    1. Dongmei Zhang
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    Correspondence to Aiguo Shen.

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    Dongmei Zhang and Hongmei Wang contributed equally to this work.

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    Zhang, D., Wang, H., Liu, H. et al. nNOS Translocates into the Nucleus and Interacts with Sox2 to Protect Neurons Against Early Excitotoxicity via Promotion of Shh Transcription. Mol Neurobiol 53, 6444–6458 (2016). https://doi.org/10.1007/s12035-015-9545-z

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