Evolution of the mammalian embryonic pluripotency gene regulatory network
Beatriz Fernandez-Tresguerres a,1, Susana Cañon a,1, Teresa Rayon a, Barbara Pernaute a,2, Miguel Crespo a,3, Carlos Torroja b, and Miguel Manzanares a,4
+Author Affiliations
aDepartment of Cardiovascular Developmental Biology and
bBioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain
↵2Present address: Molecular Embryology Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital Campus, Imperial College London, London W12 ONN, United Kingdom.
↵3Present address: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065.
Edited* by Janet Rossant, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada, and approved October 6, 2010 (received for review July 22, 2010)
↵1B.F.-T. and S.C. contributed equally to this work.
Abstract
Embryonic pluripotency in the mouse is established and maintained by a gene-regulatory network under the control of a core set of transcription factors that include octamer-binding protein 4 (Oct4; official name POU domain, class 5, transcription factor 1, Pou5f1), sex-determining region Y (SRY)-box containing gene 2 (Sox2), and homeobox protein Nanog. Although this network is largely conserved in eutherian mammals, very little information is available regarding its evolutionary conservation in other vertebrates. We have compared the embryonic pluripotency networks in mouse and chick by means of expression analysis in the pregastrulation chicken embryo, genomic comparisons, and functional assays of pluripotency-related regulatory elements in ES cells and blastocysts. We find that multiple components of the network are either novel to mammals or have acquired novel expression domains in early developmental stages of the mouse. We also find that the downstream action of the mouse core pluripotency factors is mediated largely by genomic sequence elements nonconserved with chick. In the case of Sox2 and Fgf4, we find that elements driving expression in embryonic pluripotent cells have evolved by a small number of nucleotide changes that create novel binding sites for core factors. Our results show that the network in charge of embryonic pluripotency is an evolutionary novelty of mammals that is related to the comparatively extended period during which mammalian embryonic cells need to be maintained in an undetermined state before engaging in early differentiation events.
Footnotes
4To whom correspondence should be addressed. E-mail:mmanzanares@cnic.es.
Author contributions: B.F.-T., S.C., T.R., B.P., and M.M. designed research; B.F.-T., S.C., T.R., B.P., and M.M. performed research; B.F.-T., S.C., T.R., B.P., M.C., C.T., and M.M. analyzed data; and B.F.-T., S.C., and M.M. wrote the paper.
The authors declare no conflict of interest.
↵*This Direct Submission article had a prearranged editor.
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