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Development January 1, 2011; 138 (1): 33-44.

Geminin cooperates with Polycomb to restrain multi-lineage commitment in the early embryo.

Lim JW , Hummert P , Mills JC , Kroll KL .

Transient maintenance of a pluripotent embryonic cell population followed by the onset of multi-lineage commitment is a fundamental aspect of development. However, molecular regulation of this transition is not well characterized in vivo. Here, we demonstrate that the nuclear protein Geminin is required to restrain commitment and spatially restrict mesoderm, endoderm and non-neural ectoderm to their proper locations in the Xenopus embryo. We used microarray analyses to demonstrate that Geminin overexpression represses many genes associated with cell commitment and differentiation, while elevating expression levels of genes that maintain pluripotent early and immature neurectodermal cell states. We characterized the relationship of Geminin to cell signaling and found that Geminin broadly represses Activin-, FGF- and BMP-mediated cell commitment. Conversely, Geminin knockdown enhances commitment responses to growth factor signaling and causes ectopic mesodermal, endodermal and epidermal fate commitment in the embryo. We also characterized the functional relationship of Geminin with transcription factors that had similar activities and found that Geminin represses commitment independent of Oct 4 ortholog (Oct25/60) activities, but depends upon intact Polycomb repressor function. Consistent with this, chromatin immunoprecipitation assays directed at mesodermal genes demonstrate that Geminin promotes Polycomb binding and Polycomb-mediated repressive histone modifications, while inhibiting modifications associated with gene activation. This work defines Geminin as an essential regulator of the embryonic transition from pluripotency through early multi-lineage commitment, and demonstrates that functional cooperativity between Geminin and Polycomb contributes to this process.

PubMed ID: 21098561
PMC ID: PMC2998164
Article link: Development
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: a2m foxi1 fzd7 gal.2 gmnn grhl1 hhex krt12.4 mix1 post pou5f3.2 pou5f3.3 psmd6 sall1 sox11 sox17a sox2 sox3 szl tbx2 tbxt ventx1.2 ventx2.2 xpo1 zic1 zic2 zic3
Morpholinos: ezh2 MO1 ezh2 MO2 gmnn MO1 pou5f3.2 MO2 pou5f3.3 MO1 sox2 MO1 suz12 MO1 zeb2 MO1

GEO Series: GSE25158: NCBI

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References [+] :
Akiyama, Constitutively active BMP type I receptors transduce BMP-2 signals without the ligand in C2C12 myoblasts. 1997, Pubmed