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Ets2 is required for trophoblast stem cell self-renewal.

ABSTRACT: The Ets2 transcription factor is essential for the development of the mouse placenta and for generating signals for embryonic mesoderm and axis formation. Using a conditional targeted Ets2 allele, we show that Ets2 is essential for trophoblast stem (TS) cells self-renewal. Inactivation of Ets2 results in TS cell slower growth, increased expression of a subset of differentiation-associated genes and decreased expression of several genes implicated in TS self-renewal. Among the direct TS targets of Ets2 is Cdx2, a key master regulator of TS cell state. Thus Ets2 contributes to the regulation of multiple genes important for maintaining the undifferentiated state of TS cells and as candidate signals for embryonic development.

SUBMITTER: Wen F

PROVIDER: S-EPMC2211385 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Ets2 is required for trophoblast stem cell self-renewal.

Wen Fang F Tynan John A JA Cecena Grace G Williams Roy R Múnera Jorge J Mavrothalassitis George G Oshima Robert G RG

Developmental biology 20070922 1

The Ets2 transcription factor is essential for the development of the mouse placenta and for generating signals for embryonic mesoderm and axis formation. Using a conditional targeted Ets2 allele, we show that Ets2 is essential for trophoblast stem (TS) cells self-renewal. Inactivation of Ets2 results in TS cell slower growth, increased expression of a subset of differentiation-associated genes and decreased expression of several genes implicated in TS self-renewal. Among the direct TS targets o ...[more]

PMID: 17977525

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Project description:BackgroundTrophoblast stem cells (TSCs), the precursors of trophoblast cells of placenta, possess the potential to differentiate into various trophoblastic subtypes in vitro. Establishment of extraembryonic trophoblastic lineage is preceded by the "outside versus inside" positional information in preimplantation embryos, critically synchronized by the Hippo components. Abundant expression of Hippo effector YAP in TSCs and differentiated cells with paucity of information on Hippo regulation of TSC proliferation/differentiation led us test the hypothesis that Hippo dynamics is one of the regulators of TSC proliferation/differentiation.MethodsBlastocyst-derived murine TSCs were used. Dynamics of Hippo components were analyzed using immunofluorescence, western blotting, immunoprecipitation, qRT-PCR. Interaction studies were performed using full-length and deletion constructs. BrdU incorporation assay, flow cytometry-based polyploidy analysis and confocal microscopy were used to decipher the underlying mechanism.ResultsYAP translocates to the nucleus in TSCs and utilizes its WW2 domain to interact with the PPQY motif of the stemness factor, CDX2. YAP limits TSC proliferation with associated effect on CDX2 target CyclinD1. Trophoblast giant cells (TGC) differentiation is associated with cytoplasmic retention of YAP, heightened pYAPSer127, decrease in the level of the core Hippo component, LATS1, which thereby impedes LATS1-LIMK2 association. Decreased LATS1-LIMK2 complex formation in TGCs was associated with elevated pLIMK2Thr505 as well as its target pCOFILINSer3. Precocious overexpression of LATS1 during trophoblast differentiation decreased TGC marker, Prl2c2, diminished pLIMK2Thr505 and inactive COFILIN (pCOFILINSer3) while COFILIN-phosphatase, CHRONOPHIN remained unchanged. LATS1 overexpression inhibited trophoblast endoreduplication with smaller-sized TGC-nuclei, lower ploidy level and disintegrated actin filaments. Inhibition of LIMK2 activity recapitulated the effects of LATS1 overexpression in trophoblast cells.ConclusionThese results unveil a multilayered regulation of trophoblast self-renewal and differentiation by the Hippo components.

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Ets2 is required for trophoblast stem cell self-renewal.

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Ets2 is required for trophoblast stem cell self-renewal.

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