Caspase activity mediates the differentiation of embryonic stem cells.
Embryonic stem cells (ESCs) are capable of indefinite self-renewal while retaining the ability to differentiate to any of the three germ layers that give rise to all somatic cell types. An emerging view is that a core set of transcription factors, including Oct4, Sox2, and Nanog, form a robust autoregulatory circuit that maintains ESCs in a self-renewing state. To accommodate the capacity of such cells to undergo germ layer-specific differentiation, we predicted a posttranslational mechanism that could negatively regulate these core self-renewal factors. Here we report caspase-induced cleavage of Nanog in differentiating ESCs. Stem cells lacking the Casp3 gene showed marked defects in differentiation, while forced expression of a caspase cleavage-resistant Nanog mutant in ESCs strongly promoted self-renewal. These results link a major component of the programmed cell-death pathway to the regulation of ESC development.
Fujita
Jun
J
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
Crane
Ana M
AM
Souza
Marlon K
MK
Dejosez
Marion
M
Kyba
Michael
M
Flavell
Richard A
RA
Thomson
James A
JA
Zwaka
Thomas P
TP
D000818:Animals; D053148:Caspase 3 / Q000235:genetics* / Q000378:metabolism*; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D000071317:Nanog Homeobox Protein; D015533:Transcriptional Activation; D014162:Transfection; D019076:Transgenes / Q000235:genetics
D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D053148:Caspase 3