E-cadherin and, in its absence, N-cadherin promotes Nanog expression in mouse embryonic stem cells via STAT3 phosphorylation.
We have recently shown that loss of E-cadherin in mouse embryonic stem cells (mESCs) results in significant alterations to both the transcriptome and hierarchy of pluripotency-associated signaling pathways. Here, we show that E-cadherin promotes kruppel-like factor 4 (Klf4) and Nanog transcript and protein expression in mESCs via STAT3 phosphorylation and that β-catenin, and its binding region in E-cadherin, is required for this function. To further investigate the role of E-cadherin in leukemia inhibitory factor (LIF)-dependent pluripotency, E-cadherin null (Ecad(-/-)) mESCs were cultured in LIF/bone morphogenetic protein supplemented medium. Under these conditions, Ecad(-/-) mESCs exhibited partial restoration of cell-cell contact and STAT3 phosphorylation and upregulated Klf4, Nanog, and N-cadherin transcripts and protein. Abrogation of N-cadherin using an inhibitory peptide caused loss of phospho STAT3, Klf4, and Nanog in these cells, demonstrating that N-cadherin supports LIF-dependent pluripotency in this context. We therefore identify a novel molecular mechanism linking E- and N-cadherin to the core circuitry of pluripotency in mESCs. This mechanism may explain the recently documented role of E-cadherin in efficient induced pluripotent stem cell reprogramming.
Stem Cell Biology Group, Core Technology Facility, The University of Manchester, Manchester, United Kingdom.
Kate
K
Hawkins
Lisa
L
Mohamet
Sarah
S
Ritson
Catherine L R
CL
Merry
Christopher M
CM
Ward
D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002454:Cell Differentiation; D048708:Cell Growth Processes / Q000502:physiology; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D000071317:Nanog Homeobox Protein; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
D015820:Cadherins; D018398:Homeodomain Proteins; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse