Calcium-dependent N-cadherin up-regulation mediates reactive astrogliosis and neuroprotection after brain injury

Abstract

Brain injury induces phenotypic changes in astrocytes, known as reactive astrogliosis, which may influence neuronal survival. Here we show that brain injury induces inositol 1,4,5-trisphosphate (IP 3 )-dependent Ca 2+ signaling in astrocytes, and that the Ca 2+ signaling is required for astrogliosis. We found that type 2 IP 3 receptor knockout (IP 3 R2KO) mice deficient in astrocytic Ca 2+ signaling have impaired reactive astrogliosis and increased injuryassociated neuronal death. We identified N-cadherin and pumilio 2 (Pum2) as downstream signaling molecules, and found that brain injury induces up-regulation of N-cadherin around the injured site. This effect is mediated by Ca 2+ -dependent down-regulation of Pum2, which in turn attenuates Pum2-dependent translational repression of N-cadherin. Furthermore, we show that astrocyte-specific knockout of N-cadherin results in impairment of astrogliosis and neuroprotection. Thus, astrocytic Ca 2+ signaling and the downstream function of N-cadherin play indispensable roles in the cellular responses to brain injury. These findings define a previously unreported signaling axis required for reactive astrogliosis and neuroprotection following brain injury.calcium signal | reactive astrocyte | translational repressor | stab wound A strocytes, a major type of glial cell in the brain, play essential roles not only in physiological functions, such as synaptic plasticity and hemodynamic responses (1), but also in pathophysiological conditions, such as trauma, infection, ischemia, epileptic seizures and stroke. In response to brain injury, astrocytes undergo characteristic phenotypic changes known as reactive astrogliosis, which can exert both beneficial and detrimental effects on surrounding neurons (2-4). Despite the importance of this process, the molecular mechanisms governing astrogliosis and the role of reactive astrocytes require further clarification.Injury to the brain mobilizes astrocyte-reactivating factors, including ATP, endothelin 1 (ET1), glutamate, and inflammatory cytokines, as well as mechanical stress. These factors have been shown to evoke astrocytic Ca 2+ signals not only in culture, but also in acute brain slice preparations and in the brains of live animals (5-7). These findings raise the possibility that injury to the brain evokes astrocytic Ca 2+ signals, which in turn regulate reactive astrogliosis. However, injury-induced Ca 2+ signaling in astrocytes heretofore had not been observed in vivo, and the role of Ca 2+ signaling in pathophysiological processes after brain injury was not established.In this study, we investigated the involvement of astrocytic Ca 2+ signals and underlying molecular mechanisms in reactive astrogliosis and neuroprotection after traumatic brain injury. We found that neocortical injury evokes astrocytic Ca 2+ signals, which are required for reactive astrogliosis and neuronal protection. We identified N-cadherin and pumilio 2 (Pum2) as molecules acting downstream of astrocytic Ca 2+ signals. Around the injury site, N-cadherin is u...

Time-Dependent Changes in Serum Level of Protein Biomarkers after Focal Traumatic Brain Injury

“…Increased serum levels of N-cadherin can be an indicator of neuronal and /or synaptic loss [38,39]. Similar to most of the other biomarkers, serum N-cadherin levels also showed a biphasic pattern with peaks by day 1 and 14.…”

Modeling Alexander disease with patient IPSCS reveals cellular and molecular pathology of astrocytes

“…Among the cadherin family, N-cadherin has been classified as "nerve-derived", and is known as a key CAM in the brain. N-cadherin has also been reported to be upregulated via cellular-stress signaling after brain injury by using the N-cadherin knockout model [20]. We speculated that GFAP aggregates in AxD astrocytes can evoke cellular stress and upregulated N-cadherin as a stress response.…”

Intertwining extracellular nucleotides and their receptors with Ca2+in determining adult neural stem cell survival, proliferation and final fate

“…In addition to this, the same authors have shown that astrocytic calcium signalling and the downstream function of N-cadherin, a calcium-dependent cell -cell adhesion glycoprotein, play indispensable roles in the reactive response to a neocortical stab wound injury (SWI) and, highly relevant to this review, they have linked these mechanisms to ATP signalling [124]. Specifically, they first demonstrated that brain injury induces inositol 1,4,5-trisphosphate (IP3)-dependent Ca 2þ signalling in astrocytes and that this is required for SWI-associated astrogliosis.…”

“…However, it has to be said that, since then, detection of calcium signalling has undergone significant technical improvements and that lack of sufficiently sensitive methods at those times has prevented the measurement of small, but biologically significant, early astrocytic calcium increases contributing to induction of reactive astrogliosis. In this respect, using transgenic mice that express an ultrasensitive genetically encoded Ca 2þ indicator, YC-Nano50, in an astrocyte-specific manner, Kanemaru and co-workers [124] have recently reported the in vivo visualization of spontaneous subtle and localized astrocytic Ca 2þ signals (Ca 2þ twinkles), which are preferentially displayed in fine astrocytic processes in living mice brain.…”

“…They then reasoned that proteins whose translation is regulated by Pum2 are expected to be Ca 2þ -dependently upregulated during astrogliosis and found that N-cadherin was indeed markedly increased in reactive astrocytes. In previous studies, N-cadherin and its family proteins were initially characterized by their function in cell -cell adhesion, but were subsequently found also to regulate other cellular functions, including differentiation, proliferation, cell polarization and migration, which are likely to be at the basis of the detected reactive astrogliosis [124]. Interestingly, these authors also found that the Ca 2þ -mobilizing agonists ATP and ET1 induced downregulation of Pum2 and concomitantly upregulated N-cadherin in cultured astrocytes, thus linking astrocytic calcium mobilization by purinergic signalling to reactive astrogliosis.…”