Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death.
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.
Cappuccio
Irene
I
Department of Human Physiology and Pharmacology, University of Rome La Sapienza, 00185 Rome, Italy.
Calderone
Agata
A
Busceti
Carla L
CL
Biagioni
Francesca
F
Pontarelli
Fabrizio
F
Bruno
Valeria
V
Storto
Marianna
M
Terstappen
Georg T
GT
Gaviraghi
Giovanni
G
Fornai
Francesco
F
Battaglia
Giuseppe
G
Melchiorri
Daniela
D
Zukin
R Suzanne
RS
Zukin
Suzanne
S
Nicoletti
Ferdinando
F
Caricasole
Andrea
A
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D018920:Coculture Techniques / Q000379:methods; D015536:Down-Regulation / Q000502:physiology*; D005849:Gerbillinae; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000502:physiology; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology
C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins