GATA6 levels modulate primitive endoderm cell fate choice and timing in the mouse blastocyst.
Cells of the inner cell mass (ICM) of the mouse blastocyst differentiate into the pluripotent epiblast or the primitive endoderm (PrE), marked by the transcription factors NANOG and GATA6, respectively. To investigate the mechanistic regulation of this process, we applied an unbiased, quantitative, single-cell-resolution image analysis pipeline to analyze embryos lacking or exhibiting reduced levels of GATA6. We find that Gata6 mutants exhibit a complete absence of PrE and demonstrate that GATA6 levels regulate the timing and speed of lineage commitment within the ICM. Furthermore, we show that GATA6 is necessary for PrE specification by FGF signaling and propose a model where interactions between NANOG, GATA6, and the FGF/ERK pathway determine ICM cell fate. This study provides a framework for quantitative analyses of mammalian embryos and establishes GATA6 as a nodal point in the gene regulatory network driving ICM lineage specification.
Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Nadine
N
Schrode
Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Néstor
N
Saiz
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
Stefano
S
Di Talia
Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: hadj@mskcc.org.
Anna-Katerina
AK
Hadjantonakis
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D053624:Blastocyst Inner Cell Mass / Q000166:cytology*; D002454:Cell Differentiation; D019070:Cell Lineage; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000378:metabolism; D004707:Endoderm / Q000166:cytology / Q000196:embryology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D024002:HMGB Proteins / Q000096:biosynthesis; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D000071317:Nanog Homeobox Protein; D055760:SOXF Transcription Factors / Q000096:biosynthesis
D001549:Benzamides; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse; D024002:HMGB Proteins; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; C506614:mirdametinib; D004159:Diphenylamine; D048049:Extracellular Signal-Regulated MAP Kinases