title: The survival of differentiating embryonic stem cells is dependent on the SCF-KIT pathway.
abstract: The stem cell factor (SCF)-KIT signal transduction pathway plays a role in the proliferation, differentiation and survival of a range of stem and progenitor cell types but little is known about its function in embryonic stem (ES) cells. We generated ES cells carrying a null allele of Kit as well as a knock-in allele that encodes an SCF-independent hybrid KIT receptor that can be activated by the FKBP binding drug, AP20187. KIT null ES cells die when induced to differentiate upon withdrawal of leukaemia inhibitory factor in monolayer culture. This phenotype is recapitulated in wild-type ES cells treated with a KIT-neutralising antibody and reversed in mutant cells by activation of the hybrid KIT receptor. Differentiating KIT null ES cells exhibit elevated levels of DNA laddering and reduced BCL2 expression, indicative of apoptosis. We conclude that mouse ES cell differentiation in vitro is dependent on the SCF-KIT pathway contrasting with the apparently normal differentiation of KIT null inner cell mass or epiblast cells in vivo. This discrepancy could be explained by the presence of compensatory signals in the embryo or it could lend support to the idea of a phenotypic relationship between ES cells and early germ cells.
authors.affiliation: John Hughes Bennett Laboratory, Edinburgh Cancer Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
authors.forename: Anu
authors.initials: A
authors.lastname: Bashamboo
authors.forename: A Helen
authors.initials: AH
authors.lastname: Taylor
authors.forename: Kay
authors.initials: K
authors.lastname: Samuel
authors.forename: Jean-Jacque
authors.initials: JJ
authors.lastname: Panthier
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Whetton
authors.forename: Lesley M
authors.initials: LM
authors.lastname: Forrester
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002470:Cell Survival; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D019089:Stem Cell Factor / Q000378:metabolism*; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C463061:AP20187; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit; D016559:Tacrolimus