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The Early Human Germ Cell Lineage Does Not Express SOX2 During In Vivo Development or upon In Vitro Culture¹

Centre for Human Development, Stem Cells and Regeneration,³ Human Genetics Division,⁴ and Developmental Origins of Health and Disease Division,⁵ University of Southampton, Southampton SO16 6YD, United Kingdom Department of Growth and Reproduction,⁶ Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark

ABSTRACT

NANOG, POU5F1, and SOX2 are required by the inner cell mass of the blastocyst and act cooperatively to maintain pluripotency in both mouse and human embryonic stem cells. Inadequacy of any one of them causes loss of the undifferentiated state. Mouse primordial germ cells (PGCs), from which pluripotent embryonic germ cells (EGCs) are derived, also express POU5F1, NANOG, and SOX2. Thus, a similar expression profile has been predicted for human PGCs. Here we show by RT-PCR, immunoblotting, and immunohistochemistry that human PGCs express POU5F1 and NANOG but not SOX2, with no evidence of redundancy within the group B family of human SOX genes. Although lacking SOX2, proliferative human germ cells can still be identified in situ during early development and are capable of culture in vitro. Surprisingly, with the exception of FGF4, many stem cell-restricted SOX2 target genes remained detected within the human SOX2-negative germ cell lineage. These studies demonstrate an unexpected difference in gene expression between human and mouse. The human PGC is the first primary cell type described to express POU5F1 and NANOG but not SOX2. The data also provide a new reference point for studies attempting to turn human stem cells into gametes by normal developmental pathways for the treatment of infertility.

embryonic, gamete biology, gene regulation, human, human development, human stem cell biology, primordial germ cells, SOX2

¹Supported by a UK Department of Health Clinician Scientist award (to N.A.H), Wellcome Trust project grant GR074320MA (to N.A.H.), International Research Mobility Award from the Worldwide Universities Network (to R.M.P.), and the Danish Cancer Society (to E.R.M.). R.M.P. is the recipient of an MRC Ph.D. studentship in stem cell research. L.T. is an MRC/Juvenile Diabetes Research Foundation (JDRF) Career Development Fellow in stem cell research. The authors declare no conflicts of interest.

Correspondence: ²Neil A. Hanley, Human Genetics Division, Duthie Building, Mailpoint 808, Southampton General Hospital, Tremona Rd., Southampton SO16 6YD, U.K. FAX: 44 0 23 8079 4264; e-mail: N.A.Hanley{at}soton.ac.uk