Developmental Cell
Volume 21, Issue 6, 13 December 2011, Pages 1005-1013
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Article
Primitive Endoderm Differentiates via a Three-Step Mechanism Involving Nanog and RTK Signaling

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Summary

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.

Highlights

Nanog knockdown is sufficient to specify primitive endoderm cell autonomously ► Nanog induction of Fgf4 contributes to PrE maturation in neighboring cells ► Early Gata6 expression is directly RTK dependent ► Late Gata6 expression is indirectly RTK dependent via repression of Nanog

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3

These authors contributed equally to this work

4

Present address: Department of Zoology, University of Melbourne, 3010 Victoria, Australia

5

Present address: IGF, CNRS UMR5203, INSERM U661, University of Montpellier I and II, 34095 Montpellier Cedex, France