Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions

Liu, Dong; Zhou, Jiaxi; Wang, Lu; Shin, Myung Eun; Su, Pei; Li, Xiaohua; Kuang, Haibin; Guo, Weixiang; Yang, Hong; Cheng, Linzhao; Tanaka, Tetsuya; Leckband, Deborah; Reynolds, Albert B.; Duan, Enkui; Wang, Fei

doi:10.1084/jem20712oia34

Cited by 21 publications

(33 citation statements)

References 21 publications

(28 reference statements)

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“…Our mESC findings appear at first to contradict those in an earlier report using hESCs, in which p120-catenin knockdown led to stemness loss under hESC maintenance conditions (Li et al, 2010a). Although mESCs share similarities with hESCs, they differ in several major aspects (Hirai et al, 2011).…”

Section: P120-catenin In Modulating Stemness and Differentiationcontrasting

confidence: 97%

“…The relationship between p120-catenin and E-cadherin is characterized in contexts such as cadherin stability (see Introduction) (Hatzfeld, 2005;Humphries and Reynolds, 2009;McCrea and Park, 2007;McEwen et al, 2012;Reynolds, 2007;Boggetti and Niessen, 2012). Intriguingly, E-cadherin modulates hESC differentiation in vitro, with reductions in E-cadherin levels associated with a departure from stemness (Li et al, 2010a). We thus tested whether low E-cadherin levels are functionally associated with p120-catenin-mediated RESTCoREST modulation of target genes.…”

Section: Upstream Pathway Regulation: E-cadherin Appears To Modulate mentioning

confidence: 99%

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P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation

Lee

Furuta

et al. 2014

Journal of Cell Science

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Although the canonical Wnt pathway and b-catenin have been extensively studied, less is known about the role of p120-catenin (also known as d1-catenin) in the nuclear compartment. Here, we report that p120-catenin binds and negatively regulates REST and CoREST (also known as Rcor1), a repressive transcriptional complex that has diverse developmental and pathological roles. Using mouse embryonic stem cells (mESCs), mammalian cell lines, Xenopus embryos and in vitro systems, we find that p120-catenin directly binds the REST-CoREST complex, displacing it from established gene targets to permit their transcriptional activation. Importantly, p120-catenin levels further modulate the mRNA and protein levels of Oct4 (also known as POU5F1), Nanog and Sox2, and have an impact upon the differentiation of mESCs towards neural fates. In assessing potential upstream inputs to this new p120-catenin-REST-CoREST pathway, REST gene targets were found to respond to the level of E-cadherin, with evidence suggesting that p120-catenin transduces signals between Ecadherin and the nucleus. In summary, we provide the first evidence for a direct upstream modulator and/or pathway regulating REST-CoREST, and reveal a substantial role for p120-catenin in the modulation of stem cell differentiation.

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Section: P120-catenin In Modulating Stemness and Differentiationcontrasting

confidence: 97%

Section: Upstream Pathway Regulation: E-cadherin Appears To Modulate mentioning

confidence: 99%

P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation

Lee

Furuta

et al. 2014

Journal of Cell Science

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“…For shRNA-mediated gene knockdown, pLKO vectors containing different ISL-1 shRNA sequences (Sigma-Aldrich) were used to package virus with Viralpower Lentivirus Packaging System (Invitrogen) 44,45 . To deliver ISL1-targeting shRNAs, hESCs were induced to undergo MN differentiation and infected with lentivirus containing ISL1 shRNAs before the induction of neuronal maturation (day 9) with a multiplicity of infection of B100.…”

Section: Methodsmentioning

confidence: 99%

High-efficiency motor neuron differentiation from human pluripotent stem cells and the function of Islet-1

et al. 2014

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Efficient derivation of large-scale motor neurons (MNs) from human pluripotent stem cells is central to the understanding of MN development, modelling of MN disorders in vitro and development of cell-replacement therapies. Here we develop a method for rapid (20 days) and highly efficient (B70%) differentiation of mature and functional MNs from human pluripotent stem cells by tightly modulating neural patterning temporally at a previously undefined primitive neural progenitor stage. This method also allows high-yield (4250%) MN production in chemically defined adherent cultures. Furthermore, we show that Islet-1 is essential for formation of mature and functional human MNs, but, unlike its mouse counterpart, does not regulate cell survival or suppress the V2a interneuron fate. Together, our discoveries improve the strategy for MN derivation, advance our understanding of human neural specification and MN development, and provide invaluable tools for human developmental studies, drug discovery and regenerative medicine.

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“…These proteins bind cadherins on adjacent cell surfaces to mediate cellcell adhesion and trigger signaling cascades that control differentiation, proliferation and cell migration (Bhadriraju et al, 2007;Desai et al, 2009;Fournier et al, 2008;Li et al, 2010;Liu et al, 2006;Rowlands et al, 2004;Wong and Gumbiner, 2003). The protein architecture comprises an extracellular region, which embeds the adhesive function, a transmembrane domain and a cytoplasmic domain (Yap et al, 1997a).…”

Section: Introductionmentioning

confidence: 99%

N-Glycosylation Alters Cadherin-Mediated Intercellular Binding Kinetics

Langer

Guo

Shashikanth

et al. 2012

Journal of Cell Science

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SummaryWe present direct evidence that the N-glycosylation state of neural cadherin impacts the intrinsic kinetics of cadherin-mediated intercellular binding. Micropipette manipulation measurements quantified the effect of N-glycosylation mutations on intercellular binding dynamics. The wild-type protein exhibits a two-stage binding process in which a fast, initial binding step is followed by a short lag and second, slower transition to the final binding stage. Mutations that ablate N-glycosylation at three sites on the extracellular domains 2 and 3 of neural cadherin alter this kinetic fingerprint. Glycosylation does not affect the affinities between the adhesive Nterminal domains, but instead modulates additional cadherin interactions, which govern the dynamics of intercellular binding. These results, together with previous findings that these hypo-glycosylation mutations increase the prevalence of cis dimers on cell membranes, suggest a binding mechanism in which initial adhesion is followed by additional cadherin interactions, which enhance binding but are modulated by N-glycosylation. Given that oncogene expression drives specific changes in N-glycosylation, these results provide insight into possible mechanisms altering cadherin function during tumor progression.

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Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions

Cited by 21 publications

References 21 publications

P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation

P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation

High-efficiency motor neuron differentiation from human pluripotent stem cells and the function of Islet-1

N-Glycosylation Alters Cadherin-Mediated Intercellular Binding Kinetics

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