Smoothened agonist augments proliferation and survival of neural cells.
Sonic hedgehog signaling pathway is important in developmental processes like dorsoventral neural tube patterning, neural stem cell proliferation and neuronal and glial cell survival. Shh is also implicated in the regulation of the adult hippocampal neurogenesis. Recently, nonpeptidyl Smoothened activators of the Shh pathway have been identified. The aim of this study was to investigate the effects of chlorobenzothiophene-containing molecule, Smo agonist (SAG), which has been shown to activate Shh signaling pathway, in neurogenesis and neuronal survival in in vitro and in vivo models. Our in vitro experiments showed that SAG induces increased expression of Gli1 mRNA, transcriptional target and mediator of Shh signal. In vitro experiments also demonstrated that SAG in low-nanomolar concentrations induces proliferation of neuronal and glial precursors without affecting the differentiation pattern of newly produced cells. In contrast to Shh, SAG did not induce neurotoxicity in neuronal cultures. The SAG and Shh treatment also promoted the survival of newly generated neural cells in the dentate gyrus after their intracerebroventricular administration to adult rats. We propose that SAG and similar compounds represent attractive molecules to be developed for treatment of disorders where stimulation of the generation and survival of new neural cells would be beneficial.
Bragina
Olga
O
Institute of Clinical Medicine, Tallinn University of Technology, Estonia.
Sergejeva
Svetlana
S
Serg
Martin
M
Zarkovsky
Tamara
T
Maloverjan
Alla
A
Kogerman
Priit
P
Zarkovsky
Aleksandr
A
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D003514:Cyclohexylamines / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000072086:Smoothened Receptor; D013876:Thiophenes / Q000494:pharmacology*; D000071676:Zinc Finger Protein GLI1
D003514:Cyclohexylamines; C498521:Gli1 protein, rat; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C468918:SAG compound; C491022:Smo protein, mouse; C498555:Smo protein, rat; D000072086:Smoothened Receptor; D013876:Thiophenes; D000071676:Zinc Finger Protein GLI1