Talk:Developmental Signals - Nanog

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Cite this page: Hill, M.A. (2021, May 17) Embryology Developmental Signals - Nanog. Retrieved from


Esrrb Complementation Rescues Development of Nanog-Null Germ Cells

Cell Rep. 2018 Jan 9;22(2):332-339. doi: 10.1016/j.celrep.2017.12.060.

Zhang M1, Leitch HG2, Tang WWC3, Festuccia N1, Hall-Ponsele E1, Nichols J4, Surani MA3, Smith A5, Chambers I6.


The transcription factors (TFs) Nanog and Esrrb play important roles in embryonic stem cells (ESCs) and during primordial germ-cell (PGC) development. Esrrb is a positively regulated direct target of NANOG in ESCs that can substitute qualitatively for Nanog function in ESCs. Whether this functional substitution extends to the germline is unknown. Here, we show that germline deletion of Nanog reduces PGC numbers 5-fold at midgestation. Despite this quantitative depletion, Nanog-null PGCs can complete germline development in contrast to previous findings. PGC-like cell (PGCLC) differentiation of Nanog-null ESCs is also impaired, with Nanog-null PGCLCs showing decreased proliferation and increased apoptosis. However, induced expression of Esrrb restores PGCLC numbers as efficiently as Nanog. These effects are recapitulated in vivo: knockin of Esrrb to Nanog restores PGC numbers to wild-type levels and results in fertile adult mice. These findings demonstrate that Esrrb can replace Nanog function in germ cells. KEYWORDS: PGCLCs; competence; naive pluripotency; primordial germ cells; transcription factors

PMID: 29320730 DOI: 10.1016/j.celrep.2017.12.060

The primary role of zebrafish nanog is in extra-embryonic tissue

Development. 2018 Jan 9;145(1). pii: dev147793. doi: 10.1242/dev.147793.

Gagnon JA1, Obbad K2, Schier AF1,3,4,5.


The role of the zebrafish transcription factor Nanog has been controversial. It has been suggested that Nanog is primarily required for the proper formation of the extra-embryonic yolk syncytial layer (YSL) and only indirectly regulates gene expression in embryonic cells. In an alternative scenario, Nanog has been proposed to directly regulate transcription in embryonic cells during zygotic genome activation. To clarify the roles of Nanog, we performed a detailed analysis of zebrafish nanog mutants. Whereas zygotic nanog mutants survive to adulthood, maternal-zygotic (MZnanog) and maternal mutants exhibit developmental arrest at the blastula stage. In the absence of Nanog, YSL formation and epiboly are abnormal, embryonic tissue detaches from the yolk, and the expression of dozens of YSL and embryonic genes is reduced. Epiboly defects can be rescued by generating chimeric embryos of MZnanog embryonic tissue with wild-type vegetal tissue that includes the YSL and yolk cell. Notably, cells lacking Nanog readily respond to Nodal signals and when transplanted into wild-type hosts proliferate and contribute to embryonic tissues and adult organs from all germ layers. These results indicate that zebrafish Nanog is necessary for proper YSL development but is not directly required for embryonic cell differentiation. KEYWORDS: GESTALT; Lineage tracing; MZT; Maternal-to-zygotic transition; Nanog; YSL; Yolk syncytial layer; ZGA; Zebrafish; Zygotic genome activation

PMID: 29180571 DOI: 10.1242/dev.147793


Multiple phases in regulation of Nanog expression during pre-implantation development

Dev Growth Differ. 2015 Dec;57(9):648-56. doi: 10.1111/dgd.12244. Epub 2015 Dec 14.

Komatsu K1, Fujimori T1,2.


Nanog is a key transcriptional factor for the maintenance of pluripotency of ES cells, iPS cells or cells in early mammalian embryos. The expression of Nanog is mainly localized to the epiblast in the late blastocyst. The Nanog gene expression pattern varies between embryos and between blastomeres during blastocyst formation. In this report, we traced the changes of Nanog expression in each cell in developing preimplantation mouse embryos through time-lapse observation of Nanog-GFP transgenic mouse embryos. The expression pattern of Nanog was classified into four phases depending on the developmental stage. Nanog expression started at very low levels during cleavage stages. It increased stochastically during the morula stage, but its expression level had no clear correlation with future cell fates. After the 32-cell stage, when embryos form the blastocyst cavity, Nanog expression was upregulated mainly in ICM cells while it was repressed in the future primitive endoderm lineage in an FGF signaling-dependent manner in the later stages. These results indicate that there are multiple phases in the transcriptional regulation of Nanog during blastocyst formation. © 2015 Japanese Society of Developmental Biologists. KEYWORDS: Nanog; blastocyst; preimplantation embryo; single cell; time-lapse

PMID 26660234

Reversible transformation and de-differentiation of human cells derived from induced pluripotent stem cell teratomas

Hum Cell. 2015 Jun 12. [Epub ahead of print]

Kamada M1, Mitsui Y, Matsuo T, Takahashi T.


We first aimed to generate transformed cell lines from a human induced pluripotent stem cell (hiPSC)-teratoma, and then examined the tumorigenic risks of the differentiated cells from hiPSC explant, because hiPSC-derivatives give rise to tumors in immune-deficient mice when transplanted. The colonies isolated from sparse cultures of hiPSC-teratoma cells expressed NANOG and OCT3/4 strongly, and telomerase reverse transcriptase (TERT) weakly. However, soft agar assay demonstrated that only one of them generated colonies in the gel, though hiPSCs, hTERT-transfected immortal cells, and its oncogene-transfected cells did not form any colonies. Furthermore, none of colonies isolated from the soft agar gel on primary culture (passage 0) of teratoma cells, expressed NANOG and OCT3/4 in the expanded cultures. The second soft agar assay on the colony-derived cells was unexpectedly negative. The cumulative growth curve, telomere shortening, and senescence-associated β-galactosidase (SA β-gal) staining confirmed the mortality of these cells, suggesting their reversible transformation. By using medium for embryonic stem cell (ESC medium) after MCDB 131 (MCDB) medium, the differentiated culture cells derived from hiPSC-teratoma converted into the cells expressing undifferentiated marker proteins, which lost afterwords even in ESC medium with feeder SNL76/7. The reversibility of transformation and de-differentiation suggest that tumorigenic risks of differentiated cells arise when they are exposed to suitable niches in vivo. Thus, removal of only the undifferentiated cells from iPSC-derivatives before transplantation does not solve the problem. Elucidation of mechanisms of reversibility and control of epigenetic changes is discussed as a safety bottleneck for hiPSC therapy.

PMID 26069211


Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells

Cell. 2003 May 30;113(5):643-55.

Chambers I1, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A.


Embryonic stem (ES) cells undergo extended proliferation while remaining poised for multilineage differentiation. A unique network of transcription factors may characterize self-renewal and simultaneously suppress differentiation. We applied expression cloning in mouse ES cells to isolate a self-renewal determinant. Nanog is a divergent homeodomain protein that directs propagation of undifferentiated ES cells. Nanog mRNA is present in pluripotent mouse and human cell lines, and absent from differentiated cells. In preimplantation embryos, Nanog is restricted to founder cells from which ES cells can be derived. Endogenous Nanog acts in parallel with cytokine stimulation of Stat3 to drive ES cell self-renewal. Elevated Nanog expression from transgene constructs is sufficient for clonal expansion of ES cells, bypassing Stat3 and maintaining Oct4 levels. Cytokine dependence, multilineage differentiation, and embryo colonization capacity are fully restored upon transgene excision. These findings establish a central role for Nanog in the transcription factor hierarchy that defines ES cell identity. Comment in Nanog: a new recruit to the embryonic stem cell orchestra. [Cell. 2003]

PMID 12787505