myc maintains embryonic stem cell pluripotency and self-renewal.
While endogenous Myc (c-myc) and Mycn (N-myc) have been reported to be separately dispensable for murine embryonic stem cell (mESC) function, myc greatly enhances induced pluripotent stem (iPS) cell formation and overexpressed c-myc confers LIF-independence upon mESC. To address the role of myc genes in ESC and in pluripotency generally, we conditionally knocked out both c- and N-myc using myc doubly homozygously floxed mESC lines (cDKO). Both lines of myc cDKO mESC exhibited severely disrupted self-renewal, pluripotency, and survival along with enhanced differentiation. Chimeric embryos injected with DKO mESC most often completely failed to develop or in rare cases survived but with severe defects. The essential nature of myc for self-renewal and pluripotency is at least in part mediated through orchestrating pluripotency-related cell cycle and metabolic programs. This study demonstrates that endogenous myc genes are essential for mESC pluripotency and self-renewal as well as providing the first evidence that myc genes are required for early embryogenesis, suggesting potential mechanisms of myc contribution to iPS cell formation.
Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine, Sacramento, CA 95817, USA.
Natalia V
NV
Varlakhanova
Rebecca F
RF
Cotterman
Wilhelmine N
WN
deVries
Judy
J
Morgan
Leah Rae
LR
Donahue
Stephen
S
Murray
Barbara B
BB
Knowles
Paul S
PS
Knoepfler
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D047108:Embryonic Development; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D016259:Genes, myc / Q000502:physiology*; D007124:Immunoenzyme Techniques; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015415:Biomarkers; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger