Maintaining embryonic stem cell pluripotency with Wnt signaling

Abstract

SummaryWnt signaling pathways control lineage specification in vertebrate embryos and regulate pluripotency in embryonic stem (ES) cells, but how the balance between progenitor selfrenewal and differentiation is achieved during axis specification and tissue patterning remains highly controversial. The context-and stage-specific effects of the different Wnt pathways produce complex and sometimes opposite outcomes that help to generate embryonic cell diversity. Although the results of recent studies of the Wnt/-catenin pathway in ES cells appear to be surprising and controversial, they converge on the same conserved mechanism that leads to the inactivation of TCF3-mediated repression.Key words: Embryonic stem cells, TCF, -catenin, GSK3, Pluripotency, Self-renewal, Homeodomain-interacting protein kinase Introduction A major goal of developmental and stem cell biology is to elucidate the mechanisms that allow embryonic progenitor cells to choose a specific path for differentiation or to maintain their pluripotency. Pluripotency is a common attribute of the early blastomeres of vertebrates, and is one that allows these cells to contribute to any of the three germ layers (ectoderm, mesoderm or endoderm). The derivation of pluripotent and self-renewing embryonic stem (ES) cells in the early 1980s established one of the best in vitro models of early embryonic development (Evans and Kaufman, 1981;Martin, 1981). Nevertheless, our understanding of the key pathways that lead to the ES cell-like state is far from complete, mainly due to the fact that normal blastocyst cells do not undergo the unlimited self-renewal that is observed in ES cell culture. The question of how a blastocyst cell is able to differentiate into a cell that belongs to any of the three germ layers remains unclear. However, recent progress has provided some insight into this question, with the identification of several signaling pathways that are crucial for lineage specification in the early embryo and in ES cells (Arnold and Robertson, 2009;Boyer et al., 2005;Nichols and Smith, 2011;Rossant and Tam, 2009;Schier and Talbot, 2005;Ying et al., 2008).Another critically important process in the embryo is the acquisition by cells of positional information. In the simplest case, this information corresponds to the specification of axes in the whole embryo and in specific organs. Proper positional values are essential for normal embryogenesis and need to be reconstituted during regeneration for proper organ function (Brockes and Kumar, 2008;Kragl et al., 2009). Whereas animal pole blastomeres of the Xenopus embryo appear to 'remember' their position in the embryo from which they originated (Savage and Phillips, 1989;Sokol and Melton, 1991), there is no clear evidence that such positional information exists within the mammalian blastocyst from which ES cells are derived (Arnold and Robertson, 2009;Gardner et al., 1992;Rossant and Tam, 2009). Nevertheless, some studies argue that such information can arise by a stochastic mechanism de novo, during formation o...

Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

“…Other than TCFs, Groucho/TLEs also interact with other transcriptional factors (e.g., HES1) through their C-terminal region (Grbavec et al 1998). Hikasa and Sokol 2011;Sokol 2011). Phosphorylated TCF3 exhibits a reduced DNA-binding affinity, suggesting a model in which Wnt-induced Hipk2 phosphorylation results in a depression of TCF3 target genes (Fig.…”

Pluripotency in the Embryo and in Culture

“…Moreover, the canonical Wnt/b-catenin pathway is a major inducer of axis formation and mesoderm differentiation in both the early embryo and ESC-derived embryoid bodies (ten Berge et al 2008), which would imply a radical switch in function. The relative levels of different Tcfs may change in the late epiblast, but it also seems likely that Tcf3 may be regulated by pathways other than Wnt (Sokol 2011).…”

The transcriptional regulation of pluripotency

“…mESCs are also responsive to Wnt-signalling, but whether Wnt signalling promotes self-renewal or causes mESC differentiation is still being actively debated [73,74]. Active canonical Wnt-signalling leads to the stabilisation of β-catenin, hence allowing for the association of β-catenin with the TCF/LEF family of transcription factors for gene activation [73].…”

“…Active canonical Wnt-signalling leads to the stabilisation of β-catenin, hence allowing for the association of β-catenin with the TCF/LEF family of transcription factors for gene activation [73]. Tcf3, which is the most abundant Tcf protein in mESCs [75], has been previously shown to co-localize with the core Oct4, Sox2 and Nanog-binding sites [54,76], therefore suggesting that Wnt signalling, like LIF and BMP pathways, is integrated into the ESC transcriptional regulatory core.…”

“…In mESCs, Tcf3 functions primarily as a transcriptional repressor [75,77,78] and Tcf3-null mESCs are resistant towards differentiation [75,79]. However, as the process in which Tcf3 regulates gene expression is still not clear, and with multiple models being proposed to account for the mechanism of how β-catenin and Tcf3 interaction could initiate gene expression [73], additional studies are clearly needed to define the role of Wnt-signalling in ESCs. Additionally, given that Wnt-signalling in hESCs has not been well explored, it would also be interesting to determine if similar Wnt-regulatory pathways are conserved in hESCs.…”