title: Primitive endoderm differentiates via a three-step mechanism involving Nanog and RTK signaling.
abstract: During preimplantation mouse development, the inner cell mass (ICM) differentiates into two cell lineages--the epiblast and the primitive endoderm (PrE)--whose precursors are identifiable by reciprocal expression of Nanog and Gata6, respectively. PrE formation depends on Nanog by a non-cell-autonomous mechanism. To decipher early cell- and non-cell-autonomous effects, we performed a mosaic knockdown of Nanog and found that this is sufficient to induce a PrE fate cell autonomously. Strikingly, in Nanog null embryos, Gata6 expression is maintained, showing that initiation of the PrE program is Nanog independent. Treatment of Nanog null embryos with pharmacological inhibitors revealed that RTK dependency of Gata6 expression is initially direct but later indirect via Nanog repression. Moreover, we found that subsequent expression of Sox17 and Gata4--later markers of the PrE--depends on the presence of Fgf4 produced by Nanog-expressing cells. Thus, our results reveal three distinct phases in the PrE differentiation program.
authors.affiliation: GReD; INSERM U931; CNRS UMR6247; Clermont University, 28 Place Dunant, 63001 Clermont-Ferrand, France.
authors.forename: Stephen
authors.initials: S
authors.lastname: Frankenberg
authors.forename: François
authors.initials: F
authors.lastname: Gerbe
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bessonnard
authors.forename: Corinne
authors.initials: C
authors.lastname: Belville
authors.forename: Pierre
authors.initials: P
authors.lastname: Pouchin
authors.forename: Olivier
authors.initials: O
authors.lastname: Bardot
authors.forename: Claire
authors.initials: C
authors.lastname: Chazaud
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D004707:Endoderm / Q000196:embryology* / Q000378:metabolism*; D051519:Fibroblast Growth Factor 4 / Q000235:genetics / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D000071317:Nanog Homeobox Protein; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; C484171:Gata4 protein, mouse; C494760:Gata6 protein, mouse; D024002:HMGB Proteins; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D012333:RNA, Messenger; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases