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First published online June 27, 2005
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2005-0080v1
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Submitted on February 25, 2005
Accepted on June 27, 2005

Rapid Communication

Downregulation of NANOG induces differentiation of Human Embryonic Stem Cells to Extraembryonic Lineages

Louise A Hyslop 1, Miodrag Stojkovic 1, Lyle Armstrong 1, Theresia Walter 1, Petra Stojkovic 1, Stefan Przyborski 2, Mary Herbert 3, Alison Murdoch 3, Tom Strachan 1, Majlinda Lako 1*

1 Centre for Stem Cell Biology & Developmental Genetics and Institute of Human Genetics
2 School of Biological and Biomedical Sciences, University of Durham
3 Newcastle Fertility Centre at Life, International Centre for Life

* To whom correspondence should be addressed. E-mail: majlinda.lako{at}ncl.ac.uk.


  Abstract

The homeobox transcription factor Nanog has been proposed to play a crucial role in the maintenance of the undifferentiated state of murine embryonic stem cells. A human counterpart, NANOG, has been identified but its function and localisation has not hitherto been described. We have used a combination of RNA interference and quantitative real-time PCR to study NANOG in human embryonic stem and embryonic carcinoma cells. Transfection of NANOG-specific short interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1 and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha and hCG-beta. Immunostaining of preimplantation human embryos showed that NANOG was expressed in the inner cell mass of expanded blastocysts but not in earlier stage embryos consistent with a role in the maintenance of pluripotency. Taken together our findings suggest that NANOG acts as a gatekeeper of pluripotency in human embryonic stem and carcinoma cells by preventing their differentiation to extraembryonic endoderm and trophectoderm lineages.

Key Words. NANOG, human embryonic stem cells, pluripotency, siRNA, trophectoderm, primitive endoderm




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