A Dynamic Role of TBX3 in the Pluripotency Circuitry

摘要

Highlights ? Tbx3 is not required for induction and maintenance of pluripotency ? Tbx3 is heterogeneously expressed in pluripotent cell in?vivo and in?vitro ? In?vivo Tbx3-high cells are committed to the PE; low cells commit to the epiblast ? Loss of Tbx3 leads to complex compensational processes in pluripotent stem cells Summary Pluripotency represents a cell state comprising a fine-tuned pattern of transcription factor activity required for embryonic stem cell (ESC) self-renewal. TBX3 is the earliest expressed member of the T-box transcription factor family and is involved in maintenance and induction of pluripotency. Hence, TBX3 is believed to be a key member of the pluripotency circuitry, with loss of TBX3 coinciding with loss of pluripotency. We report a dynamic expression of TBX3 in?vitro and in?vivo using genetic reporter tools tracking TBX3 expression in mouse ESCs (mESCs). Low TBX3 levels are associated with reduced pluripotency, resembling the more mature epiblast. Notably, TBX3-low cells maintain the intrinsic capability to switch to a TBX3-high state and vice versa. Additionally, we show TBX3 to be dispensable for induction and maintenance of naive pluripotency as well as for germ cell development. These data highlight novel facets of TBX3 action in mESCs. Graphical Abstract Figure options Download full-size image Download as PowerPoint slide prs.rt("abs_end"); Introduction Pluripotent stem cells (PSCs) are characterized by continuous self-renewal while maintaining the potential to differentiate into cells of all three germ layers. Great knowledge exists about the regulatory networks that maintain pluripotency and about key players that regulate differentiation. Pluripotency exists in various states, with the ground state of naive pluripotency as the most basic state of pluripotency ( Chen et?al., 2013 , Leitch et?al., 2013 and Wray et?al., 2010 ). Here, diverse signaling pathways, in concert with a combination of key transcription factors (TFs), precisely regulate ground state conditions. Diminutive changes in their expression can either destabilize or strengthen the network ( Karwacki-Neisius et?al., 2013 ). Several network TFs are heterogeneously expressed ( Chambers et?al., 2007 , Festuccia et?al., 2012 , Kalmar et?al., 2009 , MacArthur et?al., 2012 , Miyanari and Torres-Padilla, 2012 and Papatsenko et?al., 2015 ) and regulated in a highly dynamic manner to balance between stem cell self-renewal and exit from pluripotency ( Faddah et?al., 2013 and Radzisheuskaya et?al., 2013 ) as well as during somatic reprogramming ( Takahashi and Yamanaka, 2006 ). Finally, even core TFs of the pluripotency network determine the exit from stemness to early cell fate determination in a competitive manner ( Lu et?al., 2011 , Teo et?al., 2011 , Waghray et?al., 2015 and Weidgang et?al., 2013 ).