Wikipedia

Rex1

Rex1(Zfp-42) is a known marker ofpluripotency,and is usually found in undifferentiatedembryonic stem cells.In addition to being a marker forpluripotency,its regulation is also critical in maintaining a pluripotent state.[5]As the cells begin todifferentiate,Rex1 is severely and abruptly downregulated.[6]

ZFP42
Identifiers
AliasesZFP42,REX1, ZNF754, REX-1, zfp-42, Rex1, ZFP42 zinc finger protein
External IDsOMIM:614572;MGI:99187;HomoloGene:7601;GeneCards:ZFP42;OMA:ZFP42 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

132625

22702

Ensembl

ENSG00000179059

ENSMUSG00000051176

UniProt

Q96MM3

P22227

RefSeq (mRNA)

NM_001304358
NM_174900

NM_009556

RefSeq (protein)

NP_001291287
NP_777560

NP_033582

Location (UCSC)Chr 4: 188 – 188.01 MbChr 8: 43.75 – 43.76 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Discovery

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Rex1 was discovered by Hosler, BA et al. in 1989 when studying F9murineteratocarcinomastem cells.They found that these teratocarcinoma stem cells expressed high levels of Rex1, and that they resembled pluripotent stem cells of theinner cell mass(ICM).[7]Hosler, BA et al. found that these teratocarcinoma stem cells, when in the presence ofretinoic acid(RA), differentiated into nontumorigenic cells resembling extraembryonicendodermof early mouse embryos.[8]They were able to isolate the nucleotide sequence for Rex1 usingdifferential hybridizationof an F9 cell. They named it Rex1 for reduced expression 1 because there was a steady decline of itsmRNAlevels within 12 hours of the addition of RA.[8]

Structure

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Rex1 is aproteinthat in humans is encoded by theZFP42gene.[9][10]The Rex1 protein is 310 amino acids long, and has four closely spaced zinc fingers at 188–212, 217–239, 245–269, and 275–299.[7]

p38 MAPK & Mesenchymal Stem Cells

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Rex1 has been found to be critically important in maintaining proliferative state inmesenchymal stem cells(MSC), while simultaneously preventing differentiation. Bothumbilical cordblood MSC andadiposeMSC express high levels of Rex1, whilebone marrowMSC expressed low levels of Rex1. Proliferation rates are highly correlated with Rex1 expression levels, meaning high Rex1 expression is correlated with high levels of proliferation. The MSCs with weak Rex1 expression, have activatedp38 MAPKand high expression levels ofMKK3.Thus, Rex1 expression is inversely correlated withp38 MAPKactivation, and positively correlated with high proliferation rates.[11]Rex1 was found to inhibitMKK3expression, which activatesp38 MAPK.Activatedp38 MAPK,in turn, inhibits proliferation. Rex1 was also found to inhibitNOTCHandSTAT3,two transcription factors which lead to differentiation.[11]Therefore, Rex1 expression allows for high levels of proliferation, and prevents differentiation through a network of various transcription factors and protein kinases.

Embryo Development

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Tissue Derivation

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Duringembryogenesis,theinner cell mass(ICM) is separated from thetrophoblast.The stem cells derived from the ICM and trophectoderm have been found to express high levels ofOct3/4and Rex1.[12]As the ICM matures and begins to form theepiblast,and primitiveectoderm,the cells in the ICM have been found to be a heterogenous population, with varying levels of Rex1 expression. Rex1−/Oct3/4−triggers trophectoderm differentiation, while Rex1+/Oct3/4+cells predominantly differentiate into primitive endoderm andmesoderm.[13]Also, Rex1−/Oct3/4+cells differentiate into cells of primitive ectoderm, thesomatic celllineage.[14]

Gene Control

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Studies have shown thatPEG3andNespasare downstream targets of Rex1.[15]Rex1 can control the expression of Peg3 viaepigeneticchanges.YY1has been shown to be involved in setting up DNAmethylationon the maternal allele ofPEG3duringoogenesis.[16]Rex1 was found to protect the paternalallelefrom being methylated, and keep thePEG3gene unmethylated during early embryogenesis.[15]Rex1 exhibits gene control in developing embryos via its epigenetic control on genes such asPEG3,which has been identified as playing a key role in fetal growth rates[17]

Expression in Adult Tissues

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The only adult tissue Rex1 has been identified in are thetesticles.Usingin situ hybridizationit was determined that thespermatocytesin the more inner layers of the testicles are expressing Rex1.[18]Thus, the male germ cells undergoingmeiosisare the specific cells in the testicles that express Rex1. It has not been observed, however, that Rex1 is expressed in the female germ cells.

Rex1 Interactions with Other Transcription Factors

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Rex1 participates in a network of transcription factors that all work to regulate each other via varying expression levels.

Nanog

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TheNanogprotein has been found to be a transcriptional activator for theRex-1promoter, playing a key role in sustainingRex1expression. Knockdown ofNanoginembryonic stem cellsresults in a reduction ofRex-1expression, while forced expression ofNanogstimulatesRex-1expression.[5]Nanog regulates the transcription of Rex1 through 2 strong transactivation domains on the C-terminus which are required to activate the Rex1promoter.[5]

NOTCH

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Rex1 has been found to inhibit the expression ofNOTCH,thus preventing differentiation.[11]

STAT3

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Rex1 has been found to inhibit the expression ofSTAT3,thus preventing differentiation.[11]

Sox2

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Cooperative regulation of Rex1 is seen withSox2andNanog.[5]

Oct3/4

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Oct3/4can both repress and activate the Rex1 promoter. In cells that already express high level of Oct3/4, exogenously transfectedOct3/4will lead to the repression of Rex1.[19]However, in cells that are not actively expressingOct3/4,an exogenous transfection ofOct3/4will lead to the activation of Rex1.[19]This implies a dual regulatory ability ofOct3/4on Rex1. At low levels of theOct3/4protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000179059–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000051176–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^abcdShi W, Wang H, Pan G, Geng Y, Guo Y, Pei D (August 2006)."Regulation of the pluripotency marker Rex-1 by Nanog and Sox2".The Journal of Biological Chemistry.281(33): 23319–23325.doi:10.1074/jbc.M601811200.PMID16714766.
  6. ^Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH (November 2006). "A protein interaction network for pluripotency of embryonic stem cells".Nature.444(7117): 364–368.Bibcode:2006Natur.444..364W.doi:10.1038/nature05284.PMID17093407.S2CID4404796.
  7. ^ab"ZooMAb® Antibodies Frequently Asked Questions".
  8. ^abHosler BA, LaRosa GJ, Grippo JF, Gudas LJ (December 1989)."Expression of REX-1, a gene containing zinc finger motifs, is rapidly reduced by retinoic acid in F9 teratocarcinoma cells".Molecular and Cellular Biology.9(12): 5623–5629.doi:10.1128/mcb.9.12.5623.PMC363733.PMID2511439.
  9. ^Henderson JK, Draper JS, Baillie HS, Fishel S, Thomson JA, Moore H, Andrews PW (Jul 2002)."Preimplantation human embryos and embryonic stem cells show comparable expression of stage-specific embryonic antigens".Stem Cells.20(4): 329–337.doi:10.1634/stemcells.20-4-329.PMID12110702.S2CID9239873.
  10. ^"Entrez Gene: ZFP42 zinc finger protein 42 homolog (mouse)".
  11. ^abcdBhandari DR, Seo KW, Roh KH, Jung JW, Kang SK, Kang KS (May 2010). Pera M (ed.)."REX-1 expression and p38 MAPK activation status can determine proliferation/differentiation fates in human mesenchymal stem cells".PLOS ONE.5(5): e10493.Bibcode:2010PLoSO...510493B.doi:10.1371/journal.pone.0010493.PMC2864743.PMID20463961.
  12. ^Garcia-Tuñon I, Guallar D, Alonso-Martin S, Benito AA, Benítez-Lázaro A, Pérez-Palacios R, et al. (July 2011)."Association of Rex-1 to target genes supports its interaction with Polycomb function".Stem Cell Research.7(1): 1–16.doi:10.1016/j.scr.2011.02.005.PMID21530438.
  13. ^Niwa H, Miyazaki J, Smith AG (April 2000). "Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells".Nature Genetics.24(4): 372–376.doi:10.1038/74199.PMID10742100.S2CID33012290.
  14. ^Toyooka Y, Shimosato D, Murakami K, Takahashi K, Niwa H (March 2008). "Identification and characterization of subpopulations in undifferentiated ES cell culture".Development.135(5): 909–918.doi:10.1242/dev.017400.PMID18263842.S2CID24530633.
  15. ^abKim JD, Kim H, Ekram MB, Yu S, Faulk C, Kim J (April 2011)."Rex1/Zfp42 as an epigenetic regulator for genomic imprinting".Human Molecular Genetics.20(7): 1353–1362.doi:10.1093/hmg/ddr017.PMC3049358.PMID21233130.
  16. ^Kim JD, Kang K, Kim J (September 2009)."YY1's role in DNA methylation of Peg3 and Xist".Nucleic Acids Research.37(17): 5656–5664.doi:10.1093/nar/gkp613.PMC2761279.PMID19628663.
  17. ^Curley JP, Barton S, Surani A, Keverne EB (June 2004)."Coadaptation in mother and infant regulated by a paternally expressed imprinted gene".Proceedings. Biological Sciences.271(1545): 1303–1309.doi:10.1098/rspb.2004.2725.PMC1691726.PMID15306355.
  18. ^Rogers MB, Hosler BA, Gudas LJ (November 1991). "Specific expression of a retinoic acid-regulated, zinc-finger gene, Rex-1, in preimplantation embryos, trophoblast and spermatocytes".Development.113(3): 815–824.doi:10.1242/dev.113.3.815.PMID1821852.
  19. ^abBen-Shushan E, Thompson JR, Gudas LJ, Bergman Y (April 1998)."Rex-1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct-3/4 and Oct-6 binding to an octamer site and a novel protein, Rox-1, binding to an adjacent site".Molecular and Cellular Biology.18(4): 1866–1878.doi:10.1128/mcb.18.4.1866.PMC121416.PMID9528758.

Further reading

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