ASK1 inhibits astroglial development via p38 mitogen-activated protein kinase and promotes neuronal differentiation in adult hippocampus-derived progenitor cells.
The mechanisms controlling differentiation and lineage specification of neural stem cells are still poorly understood, and many of the molecules involved in this process and their specific functions are yet unknown. We investigated the effect of apoptosis signal-regulating kinase 1 (ASK1) on neural stem cells by infecting adult hippocampus-derived rat progenitors with an adenovirus encoding the constitutively active form of ASK1. Following ASK1 overexpression, a significantly larger number of cells differentiated into neurons and a substantial increase in Mash1 transcription was observed. Moreover, a marked depletion of glial cells was observed, persisting even after additional treatment of ASK1-infected cultures with potent glia inducers such as leukemia inhibitory factor and bone morphogenetic protein. Analysis of the promoter for glial fibrillary acidic protein revealed that ASK1 acts as a potent inhibitor of glial-specific gene transcription. However, the signal transducers and activators of transcription 3 (STAT3)-binding site in the promoter was dispensable, while the activation of p38 mitogen-activated protein kinase was crucial for this effect, suggesting the presence of a novel mechanism for the inhibition of glial differentiation.
Faigle
Roland
R
Department of Medical Cell Biology, Institute of Anatomy and Cell Biology, Göteborg University, Gothenburg, Sweden.
Brederlau
Anke
A
Elmi
Muna
M
Arvidsson
Yvonne
Y
Hamazaki
Tatsuo S
TS
Uramoto
Hidetaka
H
Funa
Keiko
K
D000256:Adenoviridae; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D005822:Genetic Vectors; D006624:Hippocampus / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D014161:Transduction, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases