Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Required for the Development of Ischemic Neuronal Death

Abstract

Expression of Dickkopf-1 (Dkk-1), a secreted protein that negatively modulates the Wnt pathway, was induced in the hippocampus of gerbils and rats subjected to transient global cerebral ischemia as well as in cultured cortical neurons challenged with an excitotoxic pulse. In ischemic animals, the temporal and regional pattern of Dkk-1 expression correlated with the profile of neuronal death, as assessed by Nissl staining and Dkk-1 immunostaining in adjacent hippocampal sections. Treatment of ischemic animals with either Dkk-1 antisense oligonucleotides or lithium ions (which rescue the Wnt pathway acting downstream of the Dkk-1 blockade) protected vulnerable hippocampal neurons against ischemic damage. The same treatments protected cultured cortical neurons against NMDA toxicity. We conclude that induction of Dkk-1 with the ensuing inhibition of the canonical Wnt signaling pathway is required for the development of ischemic and excitotoxic neuronal death.

β-Catenin Overexpression in the Mouse Brain Phenocopies Lithium-Sensitive Behaviors

“…In the Wnt pathway, b-catenin functions as a transcription factor regulating gene expression. Recent work suggests that the Wnt signaling pathway provides neuroprotective effects from ischemia and NMDA toxicity (Cappuccio et al, 2005), and contributes to regulating neurogenesis (Lie et al, 2005;Madsen et al, 2003). Major pharmaceutical interest in the development of novel, potent inhibitors of GSK-3 currently exists.…”

Function and biological roles of the Dickkopf family of Wnt modulators

“…Dkk1 may promote apoptosis in Alzheimer neurons by enhancing Gsk3-mediated phosphorylation of the Tau protein in b-amyloid-treated neurons (Caricasole et al, 2004). Dkk1 is also induced in neurons subjected to ischemic insults, and antisense knockdown of Dkk1 shows some protection against neuronal apoptosis (Cappuccio et al, 2005). Hence, induction of Dkk1 may be involved in an apoptosis pathway.…”

Secreted and Transmembrane Wnt Inhibitors and Activators

“…Dkk1 has also been implicated in neurodegenerative processes and induction of apoptosis after neuronal injury (Caricasole et al 2004;Cappuccio et al 2005).…”