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

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.

Focal, but not global, cerebral ischaemia causes loss of myenteric neurons and upregulation of vasoactive intestinal peptide in mouse ileum

“…), but is also ascribed a neuroprotective role in the early defence against excitotoxicity (Zhang et al . ). nNOS has not previously been studied in the periphery in regard to cerebral ischaemia, but dual roles of NO release in the ENS have been described (Sandgren et al .…”

“…The expression of nNOS gradually increases in the central nervous system after an ischaemic insult (Farkas et al 2007;Chen et al 2014;Zhang et al 2016). However, the functional consequences of this are not fully understood.…”

“…However, the functional consequences of this are not fully understood. Increased nNOS correlates positively with microvascular damage and reduced cerebral perfusion (Hsu et al 2014), but is also ascribed a neuroprotective role in the early defence against excitotoxicity (Zhang et al 2016). nNOS has not previously been studied in the periphery in regard to cerebral ischaemia, but dual roles of NO release in the ENS have been described (Sandgren et al 2003b;Lin et al 2004;Venkataramana et al 2015).…”

The Expression of NP847 and Sox2 after TBI and Its Influence on NSCs

“…However Sox2-deleted NSCs demonstrate low expression of Shh in vitro (Han et al, 2008; Favaro et al, 2009). Recently, Zhang et al demonstrated that a nNOS-Sox2 complex promoted the transcription of Shh in neurons following glutamate stimulation (Zhang et al, 2016). As shh/Gli has an important role in NSCs, we measured the expression of Shh, which showed an analogous spatio-temporal change in parallel with Sox2.…”

“…Moreover, as a nuclear transcription factor, Sox2 can regulate the transcription of downstream genes. Early research showed that sonic hedgehog (Shh) is a direct target gene of Sox2 (Zhang et al, 2016). Furthermore, it is a powerful regulator of adult hippocampus neurogenesis and is essential for the maintenance of adult stem cell properties (Cheng et al, 2015).…”