News from Wellcome Trust
...Nanog was first isolated in 2003 and identified as playing an important part in stem cell pluripotency. But scientists didn't know its exact role in the process.
In the new study, the researchers showed that Nanog acts like a conductor in charge of an orchestra of genes and proteins during the final performance. All must play at the right time in perfect harmony for the cell to 'refresh' into a pluripotent state.
Without Nanog, a stem cell cannot maintain an immortal pluripotent state. Similarly, without it, attempts to reprogram adult cells to become pluripotent fail. The protein must be present specifically during the final reprogramming phase when other key factors are already present, otherwise the cell becomes 'stuck' in a halfway state of development.
"Our research shows that this unique protein flips the last switch in a multi-step process that gives cells the very powerful property of pluripotency," said Dr Jose Silva from the Wellcome Trust Centre, who led the research.
"The next challenge is to find out exactly how Nanog influences all these other molecules."
...
"It is therefore somewhat surprising that Nanog is not represented among the minimal combinations of exogenous factors found to convert mouse somatic cells into iPS cells (Takahashi and Yamanaka, 2006). This study offers an explanation (Figure 7). Our results indicate that Nanog is in fact decisive for attaining this pluripotent ground state. However, this requirement is during the final phase of reprogramming when other key factors are already present and may be fulfilled by activation of endogenous Nanog."
"In conclusion, our findings suggest that Nanog lies at the heart of a convergent mechanism for attaining the ground state of authentic pluripotency both in embryonic development and in the final phase of somatic cell reprogramming."
Cell, Volume 138, Issue 4, 722-737, 21 August 2009
DOI: 10.1016/j.cell.2009.07.039Nanog Is the Gateway to the Pluripotent Ground State
Jose Silva 1,2,6, Jennifer Nichols 1,3,6 Thorold W. Theunissen 1,2 Ge Guo 1,2 Anouk L. van Oosten1,2 Ornella Barrandon 1,2 Jason Wray 1,2 Shinya Yamanaka 4 Ian Chambers 5 and Austin Smith 1,2
1 Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
2 Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
3 Department of Physiology, Development, and Neuroscience, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
4 Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
5 MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, King's Buildings, Edinburgh EH9 3JQ, UKSummary
Pluripotency is generated naturally during mammalian development through formation of the epiblast, founder tissue of the embryo proper. Pluripotency can be recreated by somatic cell reprogramming. Here we present evidence that the homeodomain protein Nanog mediates acquisition of both embryonic and induced pluripotency. Production of pluripotent hybrids by cell fusion is promoted by and dependent on Nanog. In transcription factor-induced molecular reprogramming, Nanog is initially dispensable but becomes essential for dedifferentiated intermediates to transit to ground state pluripotency. In the embryo, Nanog specifically demarcates the nascent epiblast, coincident with the domain of X chromosome reprogramming. Without Nanog, pluripotency does not develop, and the inner cell mass is trapped in a pre-pluripotent, indeterminate state that is ultimately nonviable. These findings suggest that Nanog choreographs synthesis of the naive epiblast ground state in the embryo and that this function is recapitulated in the culmination of somatic cell reprogramming.
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