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Cell Lineage Determination in the Mouse

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Cell Lineage Determination in the Mouse CELL STRUCTURE AND FUNCTION 26: 123–129 (2001) REVIEW © 2001 by Japan Society for Cell Biology Cell Lineage Determination in the Mouse * Catherine M. Watson and Patrick P.L. Tam Embryology Unit, Children’s Medical Research Institute, Locked Bag 23, Wentworthville, New South Wales, 2145, Australia ABSTRACT. During the peri-implantation development of the mouse embryo from the blastocyst through gastrulation, Pou5f1 (OCT-4) down-regulation is closely linked to the initial step of lineage allocation to extra- embryonic and embryonic somatic tissues. Subsequently, differentiation of the lineage precursors is subject to inductive tissue interactions and intercellular signalling that regulate cell proliferation and the acquisition of lineage-specific morphological and molecular characteristics. A notable variation of this process of lineage specifi- cation is the persistence of Pou5f1 activity throughout the differentiation of the primordial germ cells, which may underpin their ability to produce pluripotent progeny either as stem cells (embryonic germ cells) in vitro or as gametes in vivo. Nevertheless, intercellular signalling still plays a critical role in the specification of the primordial germ cells. The findings that primordial germ cells can be induced from any epiblast cells and that they share com- mon progenitors with other somatic cells provide compelling evidence for the absence of a pre-determined germ line in the mouse embryo. Key words: primordial germ cell/cardiac mesoderm/trophoblast/OCT-4 During embryonic development, progenitor cells that are Fully committed, or determined, cells can no longer be per- initially pluripotent become restricted in their potency as the suaded experimentally to change their fate. options for further differentiation are progressively limited. OCT-4 is a POU domain transcription factor encoded by the Pou5f1 gene and is expressed in the blastomeres of the cleavage stage pre-implantation embryo. Pou5f1 activity is * To whom correspondence should be addressed: Embryology Unit, maintained in the cells of the inner cell mass (ICM) of the Children’s Medical Research Institute, Locked Bag 23, Wentworthville, New South Wales, 2145, Australia. blastocyst, the epiblast of the peri-implantation embryo and Fax: +61-2-9687-2120 in the primordial germ cells (PGC) of the early organogene- E-mail: [email protected]; [email protected] sis embryo. The inner cell mass and the epiblast have been Abbreviations: Akp2, alkaline phosphatase 2, liver (TNAP tissue non- specific alkaline phosphatase); Ascl2, (Mash2) achaete-scute complex ho- shown by lineage analysis to be the sole source of progeni- molog-like (Drosophila); BMP, bone morphogenetic protein; bHLH, basic tors of all types of somatic tissues in the fetal body as well helix-loop-helix; Cdh1, E-cadherin; Cdx2, caudal type homeo box 2; Dkk1, as the PGCs (Gardner and Beddington, 1988). dickkopf homolog 1 (Xenopus laevis); eed, embryonic ectoderm develop- Female primordial germ cells give rise to oocytes, which ment; E, embryonic day; Eomes, eomesodermin homolog (Xenopus laevis); EPL, primitive ectoderm-like; Esrrb, estrogen related receptor, display the full potency to form all types of tissues of the re- beta; ES, embryonic stem; Esx1, extraembryonic, spermatogenesis, sultant conceptus upon fertilization by the sperm derived homeobox 1; FGF, fibroblast growth factor and Fgfr2 fibroblast growth from the male primordial germ cells, or when activated par- factor receptor 2; Flt, FMS-like tyrosine kinase; FOG, Friend of GATA; Foxa2, forkhead box A2; GATA, GATA-binding protein; Hand, heart and thenogenetically. Furthermore, pluripotent stem cells which neural crest derivatives expressed transcript; ICM, inner cell mass; Kit,(C- can be derived in vitro from the ICM [as embryonic stem Kit) kit oncogene; LIF, leukemia inhibiting factor; Lhx1, LIM homeobox (ES) cells] or the PGCs [as embryonic germ (EG) cells], can protein 1; MADS, MCM1, agamous, deficiens, serum response factor; contribute to every type of somatic cell and PGCs of the Mef2, myocyte enhancer factor; Mesp1, mesoderm posterior 1; Mesp2, mesoderm posterior 2; MyoD, myogenic differentiation; Nkx2-5,NK2 chimaeric embryo (see Tada and Tada this issue). transcription factor related, locus 5 (Drosophila); OCT-4, octamer-4 prod- These properties of the Pou5f1 (OCT-4) expressing cells uct of POU domain, class 5, transcription factor 1, Pou5f1 gene; Pem, are consistent with the notion that the activity of this tran- placentae and embryos oncofetal gene; PGC, primordial germ cell; Pl1, scription factor is linked to the maintenance of lineage placental lactogen 1; POU, Pit-Oct-Unc; Traf3, Tnf receptor-associated factor 3 (amn); Tbn, taube nuss; TS, trophoblast stem; Wnt, wingless- pluripotency. Of specific interest is that Pou5f1 activity is related MMTV integration site. always down-regulated in ES and EG cells upon in vitro dif- 123 C.M. Watson and P.P.L. Tam ferentiation and also in the somatic descendants of the inner trophoblast giant cells and the extraembryonic ectoderm cell mass and the epiblast (Pesce and Schöler, 2000). This (Rossant, 1986). The proliferation and differentiation of the raises the possibility that suppression of Pou5f1activity may polar trophectoderm have been shown to be dependent on be essential for the onset of lineage specification and cell the inductive interaction with the ICM and on the signalling differentiation (Yeom et al., 1996). Concordant with this activity of FGF4, a fibroblast growth factor protein that is prediction is the finding that absent or low level OCT-4 ex- expressedinICMderivatives. pression in ES cells biases the differentiation of the ES cells In embryos that lack FGF4 activity, the ICM degenerates, to trophectoderm (Nichols et al., 1998) which seems to re- and the trophectoderm ceases proliferation and undergoes capitulate the lack of Pou5f1 activity in the trophectoderm giant cell transformation (Feldman et al., 1994). FGF4 and of the blastocyst. OCT-4, in partnership with LIF, may act Tbn (Taube nuss) which are required for survival of the as a repressor of the activity of genes associated with ICM (Voss et al., 2000), may indirectly influence the differ- trophectoderm differentiation and an activator of other entiation of the polar trophectoderm. Actively proliferating genes that maintain pluripotency (Niwa et al., 2000). Con- cells that adopt a stable epithelial morphology have been versely, an elevation of OCT-4 expression triggers ES cell isolated from the trophectoderm in vitro inthepresenceof differentiation not to trophectoderm but instead to visceral high levels of FGFs (Tanaka et al., 1998). Removal of endoderm and mesoderm (Niwa et al., 2000). Modulation of FGF4 from the culture medium or the omission of primary OCT-4 expression in pluripotent embryonic cells therefore mouse embryonic fibroblast feeder cells from the TS culture plays a crucial role in directing their descendants along leads to differentiation of the epitheloid TS cells into specific paths of differentiation and represents the first step trophoblast giant cells (Tanaka et al., 1998). of lineage specification. FGF is also essential for trophoblast differentiation in ad- ES cells have been shown to remain pluripotent under in dition to its effect on cell proliferation (Tanaka et al., 1998; vitro culture conditions that promote the acquisition of an Rassoulazadegan et al., 2000). In the intact blastocyst, epithelial morphology (EPL cells) (Rathjen et al., 1999). If phagocytic activity is highest in the mural trophectodermal the transition from ES to EPL is equivalent to the develop- cells that are furthest from the ICM. Mural trophectoderm ment of ICM to epiblast in the peri-implantation embryo, cells continue to display characteristic phagocytic activity this may suggest that the ICM derivatives will remain pluri- when they are cultured in vitro. However, addition of FGF4 potent until the onset of gastrulation. Major decisions about and serum derived factors or co-culturing with ES cells in- lineage allocation and cell fate are made during the forma- hibits the phagocytic activity of the mural trophectoderm, tion of the germ layers during gastrulation, between E6.25– and they behave more like the polar trophectodermal cells 7.5. As cells pass through the primitive streak they are allo- that are presumably subject to a stronger influence of FGF cated to one of two germ layers, endoderm or mesoderm. in the embryo (Tanaka et al., 1998; Rassoulazadegan et al., The potency of the cells of each layer becomes restricted 2000). after passage through the streak (Davidson et al., 1999). Amongst the various cell lineages that are established in the Activity of regulatory genes is indicative of trophoblast post-gastrulation stage embryos, the PGCs are the only cells differentiation that retain OCT-4 expression and continue to express the During the differentiation of the extraembryonic transcription factor at a low level in fully grown oocytes ectoderm to trophoblastic giant cells, Fgfr2, Esrrb and Cdx2 (Pesce and Schöler, 2000). activities are down-regulated whereas Pl1 expression is In this review, we will examine the specific factors in- elevated (Table I) (Tanaka et al., 1998). Complete loss of volved in determination of cell lineages in mouse embryos Cdx2 activity results in the lack of trophoblast differentia- after their initial specification. We focus on the trophecto- tion and the mutant embryo fails to implant in the uterus derm, which is the first cell type that
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