Id1 maintains embryonic stem cell self-renewal by up-regulation of Nanog and repression of Brachyury expression.
Understanding the mechanism by which embryonic stem (ES) cells self-renew is crucial for the realization of their therapeutic potential. Earlier, overexpression of Id proteins was shown to be sufficient to maintain mouse ES cells in a self-renewing state even in the absence of serum. Here, we use ES cells derived from Id deficient mice to investigate the requirement for Id proteins in maintaining ES cell self-renewal. We find that Id1(-/-) ES cells have a defect in self-renewal and a propensity to differentiate. We observe that chronic or acute loss of Id1 leads to a down-regulation of Nanog, a critical regulator of self-renewal. In addition, in the absence of Id1, ES cells express elevated levels of Brachyury, a marker of mesendoderm differentiation. We find that loss of both Nanog and Id1 is required for the up-regulation of Brachyury, and ectopic Nanog expression in Id1(-/-) ES cells rescues the self-renewal defect, indicating that Nanog is the major downstream target of Id1. These results identify Id1 as a critical factor in the maintenance of ES cell self-renewal and suggest a plausible mechanism for its control of lineage commitment.
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Elizabeth E
EE
Romero-Lanman
Svetlana
S
Pavlovic
Bhishma
B
Amlani
Yvette
Y
Chin
Robert
R
Benezra
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D003470:Culture Media / Q000378:metabolism; D046149:Embryo Culture Techniques / Q000379:methods; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071317:Nanog Homeobox Protein; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000098908:Brachyury Protein
D015415:Biomarkers; D003470:Culture Media; D005326:Fetal Proteins; D018398:Homeodomain Proteins; D051798:Inhibitor of Differentiation Protein 1; D000071317:Nanog Homeobox Protein; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein; C497455:Idb1 protein, mouse; C475540:Nanog protein, mouse