ZO‐1 Regulates Erk, Smad1/5/8, Smad2, and RhoA Activities to Modulate Self‐Renewal and Differentiation of Mouse Embryonic Stem Cells123. (20th August 2012)

• Record Type: Journal Article
• Authors: Xu, Jianliang; Lim, Sophia Beng Hui; Ng, Mei Yong; Ali, Safiah Mohamed; Kausalya, Jaya P.; Limviphuvadh, Vachiranee; Maurer‐Stroh, Sebastian; Hunziker, Walter
• Is Part Of: Stem cells. Volume 30:Number 9(2012)
• Page Start: 1885
• Page End: 1900
• Publication Date: 2012-08-20
• Subjects: Cell lineage -- Cell polarity -- Cellular structures -- Differentiation -- Embryonic stem cells -- Signal transduction -- Stem cell research -- Tight junctions; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.1172
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: ZO‐1/Tjp1 is a cytosolic adaptor that links tight junction (TJ) transmembrane proteins to the actin cytoskeleton and has also been implicated in regulating cell proliferation and differentiation by interacting with transcriptional regulators and signaling proteins. To explore possible roles for ZO‐1 in mouse embryonic stem cells (mESCs), we inactivated the ZO‐1 locus by homologous recombination. The lack of ZO‐1 was found to affect mESC self‐renewal and differentiation in the presence of leukemia‐inhibiting factor (LIF) and Bmp4 or following removal of the growth factors. Our data suggest that ZO‐1 suppresses Stat3 and Smad1/5/8 activities and sustains extracellular‐signal‐regulated kinase (Erk) activity to promote mESC differentiation. Interestingly, Smad2, critical for human but not mESC self‐renewal, was hyperactivated in ZO‐1 −/− mESCs and RhoA protein levels were concomitantly enhanced, suggesting attenuation of the noncanonical transforming growth factor β (Tgfβ)/Activin/Nodal pathway that mediates ubiquitination and degradation of RhoA via the TJ proteins Occludin, Par6, and Smurf1 and activation of the canonical Smad2‐dependent pathway. Furthermore, Bmp4‐induced differentiation of mESCs in the absence of LIF was suppressed in ZO‐1 −/− mESCs, but differentiation down the neural or cardiac lineages was not disturbed. These findings reveal novel roles for ZO‐1 in mESC self‐renewal, pluripotency, and differentiation by influencing several signaling networks that regulate these processes. Possible implications for the differing relevance of Smad2 in mESC and human ESC self‐renewal and how ZO‐1 may connect to the different pathways are discussed. Stem Cells 2012;30:1885–1900