Developmental Signals - Nanog

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Introduction

Human testis NANOG expression[1]

NANOG plays a central role in regulating self-renewal in pluripotent stem cells and tumor cells. Human NANOG is a transcription factor protein of 305 amino acids with a conserved homeodomain motif that is localized to the nucleus.

First identified in mouse ES cells in a 2003 study[2], the author (Chambers) named the factor after an Irish myth, Tír na nÓg ("Land of the Young") as it makes stem cells immortal.



Stem Cell Links: Introduction | Timeline | Placental Cord Blood | Adult | Induced | Yamanaka Factors | Somatic Cell Nuclear Transfer | Ethics | Organoids | Category:Stem Cell


Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular

Some Recent Findings

STAP now discredited.
  • Estrogen-related receptor-beta (Esrrb) Complementation Rescues Development of Nanog-Null Germ Cells[3] "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." OMIM - ESRRB
  • The primary role of zebrafish nanog is in extra-embryonic tissue[4] "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." Zebrafish Development | Yolk Sac
  • Multiple phases in regulation of Nanog expression during pre-implantation development[5] "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." Morula | Blastocyst | Mouse Development
  • Phosphorylation stabilizes Nanog by promoting its interaction with Pin1[6] "Here we show that Nanog, a transcription factor crucial for the self-renewal of ESCs, is phosphorylated at multiple Ser/Thr-Pro motifs. This phosphorylation promotes the interaction between Nanog and the prolyl isomerase Pin1, leading to Nanog stabilization by suppressing its ubiquitination. Inhibition of Pin1 activity or disruption of Pin1-Nanog interaction in ESCs suppresses their capability to self-renew and to form teratomas in immunodeficient mice. Therefore, in addition to the stringent transcriptional regulation of Nanog, the expression level of Nanog is also modulated by posttranslational mechanisms."
  • Nanog variability and pluripotency regulation of embryonic stem cells[7] "The expression of the transcription factors Oct4, Sox2, and Nanog is commonly associated with pluripotency of mouse embryonic stem (ES) cells. However, recent observations suggest that ES cell populations are heterogeneous with respect to the expression of Nanog and that individual ES cells reversibly change their Nanog expression level."
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Human NANOG Family

Nanog belongs to the NKL subclass homeoboxes and pseudogenes.


Table - Human Nanog Family - pseudogenes
Approved
Symbol
Approved Name Previous Symbols Chromosome
NANOG Nanog homeobox FLJ12581, FLJ40451 12p13.31
NANOG P1 Nanog homeobox pseudogene 1 NANOG2 12p13.31
NANOG P2 Nanog homeobox pseudogene 2 NANOGP4 2q36.1
NANOG P3 Nanog homeobox pseudogene 3 6p12.1
NANOG P4 Nanog homeobox pseudogene 4 NANOGP2 7p14.3
NANOG P5 Nanog homeobox pseudogene 5 9q31.1
NANOG P6 Nanog homeobox pseudogene 6 10q24.2
NANOG P7 Nanog homeobox pseudogene 7 NANOGP3 14q32.12
NANOG P8 Nanog homeobox retrogene P8 15q14
NANOG P9 Nanog homeobox pseudogene 9 Xq12
NANOG P10 Nanog homeobox pseudogene 10 Xp11.3
NANOG P11 Nanog homeobox pseudogene 11 6q25.2
    Links: Developmental Signals - Nanog | OMIM | HGNC | Tbx Family


Human NANOG Family  
Table - Human Nanog Family - pseudogenes
Approved
Symbol
Approved Name Previous Symbols Chromosome
NANOG Nanog homeobox FLJ12581, FLJ40451 12p13.31
NANOG P1 Nanog homeobox pseudogene 1 NANOG2 12p13.31
NANOG P2 Nanog homeobox pseudogene 2 NANOGP4 2q36.1
NANOG P3 Nanog homeobox pseudogene 3 6p12.1
NANOG P4 Nanog homeobox pseudogene 4 NANOGP2 7p14.3
NANOG P5 Nanog homeobox pseudogene 5 9q31.1
NANOG P6 Nanog homeobox pseudogene 6 10q24.2
NANOG P7 Nanog homeobox pseudogene 7 NANOGP3 14q32.12
NANOG P8 Nanog homeobox retrogene P8 15q14
NANOG P9 Nanog homeobox pseudogene 9 Xq12
NANOG P10 Nanog homeobox pseudogene 10 Xp11.3
NANOG P11 Nanog homeobox pseudogene 11 6q25.2
    Links: Developmental Signals - Nanog | OMIM | HGNC | Tbx Family


Links: HGNC - NKL subclass homeoboxes

Classification

Functions

Required for embryonic stem cell self-renewal.

Blastocyst - Inner Cell Mass

In the early mouse embryo, Nano expression appears to be related to maintain of pluripotency in the blastocyst inner cell mass epiblast layer.[5]

Nanog expression pattern four phases:

  1. cleavage stages - very low levels
  2. morula stage - increased stochastically, no correlation with future cell fates.
  3. blastocyst stage (after 32-cell stage) - inner cell mass expression was up-regulated.
  4. blastocyst stage onwards - primitive endoderm repressed in an FGF signalling-dependent manner.


Links: Morula | Blastocyst | Mouse Development | FGF

Spermatogenesis

The cartoons below show nanog expression in mouse and dog during spermatogenesis.[1]

Mouse- spermatozoa NANOG expression.jpg Each column represents the combination of different cell types that are present in seminiferous tubules at that specific stage.

Cell types that express NANOG are outlined in red and cell types that do not express NANOG have black and grey symbols.

Legend

  • 1–16 = steps in spermiogenesis
  • In = intermediate spermatogonia
  • B = type B spermatogonia
  • Pl = pre-leptotene stage
  • L = leptotene stage
  • Z = zygotene stage
  • P = pachytene stage
  • D = diplotene stage
  • 2nd = generation of secondary spermatocytes
  • Roman figures = stage of the epithelial cycle
Dog- spermatozoa NANOG expression.jpg

Signaling Pathway

Two-level process for the induction of stem cell differentiation[7]
Two-level process for the induction of stem cell differentiation[7]

References

  1. 1.0 1.1 Kuijk EW, de Gier J, Lopes SM, Chambers I, van Pelt AM, Colenbrander B & Roelen BA. (2010). A distinct expression pattern in mammalian testes indicates a conserved role for NANOG in spermatogenesis. PLoS ONE , 5, e10987. PMID: 20539761 DOI.
  2. <pubmed>12787505</pubmed>
  3. Zhang M, Leitch HG, Tang WWC, Festuccia N, Hall-Ponsele E, Nichols J, Surani MA, Smith A & Chambers I. (2018). Esrrb Complementation Rescues Development of Nanog-Null Germ Cells. Cell Rep , 22, 332-339. PMID: 29320730 DOI.
  4. Gagnon JA, Obbad K & Schier AF. (2018). The primary role of zebrafishnanogis in extra-embryonic tissue. Development , 145, . PMID: 29180571 DOI.
  5. 5.0 5.1 Komatsu K & Fujimori T. (2015). Multiple phases in regulation of Nanog expression during pre-implantation development. Dev. Growth Differ. , 57, 648-56. PMID: 26660234 DOI.
  6. Moretto-Zita M, Jin H, Shen Z, Zhao T, Briggs SP & Xu Y. (2010). Phosphorylation stabilizes Nanog by promoting its interaction with Pin1. Proc. Natl. Acad. Sci. U.S.A. , 107, 13312-7. PMID: 20622153 DOI.
  7. 7.0 7.1 7.2 Glauche I, Herberg M & Roeder I. (2010). Nanog variability and pluripotency regulation of embryonic stem cells--insights from a mathematical model analysis. PLoS ONE , 5, e11238. PMID: 20574542 DOI.

Reviews

Blinka S & Rao S. (2017). Nanog Expression in Embryonic Stem Cells - An Ideal Model System to Dissect Enhancer Function. Bioessays , 39, . PMID: 28977693 DOI.

Marucci L. (2017). Nanog Dynamics in Mouse Embryonic Stem Cells: Results from Systems Biology Approaches. Stem Cells Int , 2017, 7160419. PMID: 28684962 DOI.

Zhang W, Sui Y, Ni J & Yang T. (2016). Insights into theNanoggene: A propeller for stemness in primitive stem cells. Int. J. Biol. Sci. , 12, 1372-1381. PMID: 27877089 DOI.

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Cite this page: Hill, M.A. (2019, September 18) Embryology Developmental Signals - Nanog. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Signals_-_Nanog

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