Synthetic small molecules that control stem cell fate.
In an attempt to better understand and control the processes that regulate stem cell fate, we have set out to identify small molecules that induce neuronal differentiation in embryonic stem cells (ESCs). A high-throughput phenotypic cell-based screen of kinase-directed combinatorial libraries led to the discovery of TWS119, a 4,6-disubstituted pyrrolopyrimidine that can induce neurogenesis in murine ESCs. The target of TWS119 was shown to be glycogen synthase kinase-3beta (GSK-3beta) by both affinity-based and biochemical methods. This study provides evidence that GSK-3beta is involved in the induction of mammalian neurogenesis in ESCs. This and such other molecules are likely to provide insights into the molecular mechanisms that control stem cell fate, and may ultimately be useful to in vivo stem cell biology and therapy.
Ding
Sheng
S
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Wu
Tom Y H
TY
Brinker
Achim
A
Peters
Eric C
EC
Hur
Wooyoung
W
Gray
Nathanael S
NS
Schultz
Peter G
PG
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D002845:Chromatography; D003598:Cytoskeletal Proteins / Q000378:metabolism; D017930:Genes, Reporter / Q000235:genetics; D007150:Immunohistochemistry; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction; D016622:Silver Staining; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology*; D020349:Surface Plasmon Resonance; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D008024:Ligands; D011743:Pyrimidines; D011758:Pyrroles; D015534:Trans-Activators; D051176:beta Catenin