Expression of a mutant retinoic acid receptor beta alters lineage differentiation in mouse embryonic stem cells.
We have introduced 1 to 2 copies of a deletion mutant (betaDeltaC) of the human retinoic acid receptor beta into mouse embryonic stem (ES) cells. The betaDeltaC-expressing cells were 10 to 100 times less sensitive to RA-induced differentiation in comparison with their parental cells. In the presence of 10(-7) M RA in monolayer culture, they showed no growth arrest or differentiation, but remained pluripotent. Embryoid bodies (EBs) derived from betaDeltaC-expressing cells differentiated into cardiomyocytes rather than neurons after treatment with 10(-6) M RA, and became neurons upon exposure to 10(-5) or 10(-4) M RA. Remarkably, after 10 passages of continuous culture in the presence of 10(-7) M RA, they still were able to form chimeras after injection into blastocysts. These data suggest that appropriate levels of normal retinoid receptors are crucial for lineage-specific differentiation of mouse ES cells in vitro. The betaDeltaC mutant protein may prove to be useful in promoting "stemness" of ES cells in culture.
Chatzi
Christina
C
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen , Foresterhill, Aberdeen, United Kingdom.
van den Brink
Christina E
CE
van der Saag
Paul T
PT
McCaig
Colin D
CD
Shen
Sanbing
S
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D014212:Tretinoin