Geminin Restrains Mesendodermal Fate Acquisition of Embryonic Stem Cells and is Associated with Antagonism of Wnt Signaling and Enhanced Polycomb-Mediated Repression

Caronna, Elizabeth A.; Patterson, Emily S.; Hummert, Pamela M.; Kroll, Kristen L.

doi:10.1002/stem.1410

Cited by 19 publications

(26 citation statements)

References 53 publications

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“…Loss of Gmnn in mouse embryos can reduce the numbers of NPCs and either reduce or increase differentiated neurons depending on the marker assayed (Emmett and O’Shea, 2012; Patterson et al, 2014; Schultz et al, 2011; Spella et al, 2011). These differential effects are likely due to Gmnn’s ability to affect the epigenetic state of NSCs (Caronna et al, 2013; Seo et al, 2007; Yellajoshyula et al, 2012). As both frog and mouse Foxd4 affect gmnn expression in Xenopus neural ectoderm, it will be important to investigate their specific molecular relationships during neural fate acquisition.…”

Section: Discussionmentioning

confidence: 99%

Foxd4 is essential for establishing neural cell fate and for neuronal differentiation

Sherman

Karpinski

Fralish

et al. 2017

Genesis

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Many molecular factors required for later stages of neuronal differentiation have been identified; however, much less is known about the early events that regulate the initial establishment of the neuroectoderm. We have used an in vitro embryonic stem cell differentiation model to investigate early events of neuronal differentiation, and to define the role of mouse Foxd4, an orthologue of a forkhead-family transcription factor central to Xenopus neural plate/neuroectodermal precursor development. We found that Foxd4 is a necessary regulator of the transition from pluripotent ES cell to neuroectodermal stem cell, and its expression is necessary for neuronal differentiation. Mouse Foxd4 expression is not only limited to the neural plate, but it is also expressed and apparently functions to regulate neurogenesis in the olfactory placode. These in vitro results suggest that mouse Foxd4 has a similar function to its Xenopus orthologue; this was confirmed by successfully substituting murine Foxd4 for its amphibian counterpart in overexpression experiments. Thus, Foxd4 appears to regulate the initial steps in establishing neuroectodermal precursors during initial development of the nervous system.

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Section: Discussionmentioning

confidence: 99%

Foxd4 is essential for establishing neural cell fate and for neuronal differentiation

Sherman

Karpinski

Fralish

et al. 2017

Genesis

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“…Little is known regarding the molecular mechanism underlying geminin-mediated tumorigenesis and cancer metastasis. Of note, contradictory reports have proposed positive and negative roles for geminin in regulating epithelial-to-mesenchymal transition during development (28,29).…”

Section: Introductionmentioning

confidence: 99%

Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis

Zhang¹,

Cai²,

Gong³

et al. 2017

Journal of Clinical Investigation

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“…Geminin is essential for neuronal differentiation in the epiblast [23], but not in neural stem cells and subsequent neurogenesis [24,25]. Some studies concluded that geminin promotes the epithelial to mesenchymal transition [21,26], whereas others concluded that it restrains mesendodermal fate acquisition [7].…”

Section: Introductionmentioning

confidence: 99%

Geminin is Essential to Prevent DNA Re-Replication-Dependent Apoptosis in Pluripotent Cells, but not in Differentiated Cells

et al. 2015

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Geminin is a dual-function protein unique to multicellular animals with roles in modulating gene expression and preventing DNA re-replication. Here, we show that geminin is essential at the beginning of mammalian development to prevent DNA re-replication in pluripotent cells, exemplified by embryonic stem cells, as they undergo self-renewal and differentiation. Embryonic stem cells, embryonic fibroblasts, and immortalized fibroblasts were characterized before and after geminin was depleted either by gene ablation or siRNA. Depletion of geminin under conditions that promote either self-renewal or differentiation rapidly induced DNA rereplication, followed by DNA damage, then a DNA damage response, and finally apoptosis. Once differentiation had occurred, geminin was no longer essential for viability, although it continued to contribute to preventing DNA re-replication induced DNA damage. No relationship was detected between expression of geminin and genes associated with either pluripotency or differentiation. Thus, the primary role of geminin at the beginning of mammalian development is to prevent DNA re-replication-dependent apoptosis, a role previously believed essential only in cancer cells. These results suggest that regulation of gene expression by geminin occurs only after pluripotent cells differentiate into cells in which geminin is not essential for viability. STEM CELLS 2015;33:3239-3253 SIGNIFICANCE STATEMENTGeminin is a dual-function protein unique to multicellular animals with roles in modulating gene expression and preventing DNA re-replication. Although geminin is essential at the beginning of mouse development, its precise role remains enigmatic. Previous studies have suggested that geminin is required to regulate expression of critical genes. Here we report the unanticipated discovery that embryonic stem cells, like some cancer cells, require geminin to prevent DNA re-replication dependent apoptosis, a characteristic that is lost during cell differentiation. DNA re-replication results in DNA damage, which in the case of pluripotent cells and some cancer cells, results in apoptosis. Other cells, such as fibroblasts, respond to DNA damage by arresting cell proliferation while they attempt to repair the damage. ESCs, as well as induced pluripotent stem cells, are widely used to model early embryonic events, provide a vehicle for introducing new or altered genes into specific mammalian tissues, and form the basis of cell replacement therapies. ESCs also exhibit characteristics of cancer cells, and our discovery that geminin is essential in ESCs to prevent DNA re-replication dependent apoptosis enhances the similarity between these two cell types, a similarity that should not be ignored.

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Geminin Restrains Mesendodermal Fate Acquisition of Embryonic Stem Cells and is Associated with Antagonism of Wnt Signaling and Enhanced Polycomb-Mediated Repression

Cited by 19 publications

References 53 publications

Foxd4 is essential for establishing neural cell fate and for neuronal differentiation

Foxd4 is essential for establishing neural cell fate and for neuronal differentiation

Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis

Geminin is Essential to Prevent DNA Re-Replication-Dependent Apoptosis in Pluripotent Cells, but not in Differentiated Cells

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