464:. In mouse, mutations in a gene of interest can be introduced retrovirally into cultured ES cells, and these can be reintroduced into the ICM of an intact embryo. The result is a chimeric mouse, which develops with a portion of its cells containing the ES cell genome. The aim of such a procedure is to incorporate the mutated gene into the germ line of the mouse such that its progeny will be missing one or both alleles of the gene of interest. Geneticists widely take advantage of this ICM manipulation technique in studying the function of genes in the mammalian system.
42:
436:
unclear, and current research seeks to identify earlier markers of asymmetry. For example, some research correlates the first two cleavages during embryogenesis with respect to the prospective animal and vegetal poles with ultimate specification. The asymmetric division of epigenetic information during these first two cleavages, and the orientation and order in which they occur, may contribute to a cell's position either inside or outside the morula.
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such a polarity during compaction is thought to generate an environmental identity for inside and outside cells of the embryo. Consequently, stochastic expression of the above transcription factors is amplified into a feedback loop that specifies outside cells to a TE fate and inside cells to an ICM fate. In the model, an apical environment turns on
280:
transcription factors and signaling molecules direct blastomere asymmetric divisions leading to what are known as inside and outside cells and thus cell lineage specification. However, due to the variability and regulative nature of mammalian embryos, experimental evidence for establishing these early fates remains incomplete.
263:
the formation of a polarized blastocyst with the ICM attached to the trophectoderm at one end (see figure). This difference in cellular localization causes the ICM cells exposed to the fluid cavity to adopt a primitive endoderm (or hypoblast) fate, while the remaining cells adopt a primitive ectoderm (or epiblast) fate. The
262:
The ICM and the TE will generate distinctly different cell types as implantation starts and embryogenesis continues. Trophectoderm cells form extraembryonic tissues, which act in a supporting role for the embryo proper. Furthermore, these cells pump fluid into the interior of the blastocyst, causing
258:
of roughly 32 cells. In mice, about 12 internal cells comprise the new inner cell mass and 20 – 24 cells comprise the surrounding trophectoderm. There is variation between species of mammals as to the number of cells at compaction with bovine embryos showing differences related to compaction as early
399:
loop that strengthens the ICM to TE cellular allocation. Initial polarization of blastomeres occurs at the 8-16 cell stage. An apical-basolateral polarity is visible through the visualization of apical markers such as Par3, Par6, and aPKC as well as the basal marker E-Cadherin. The establishment of
245:
The physical and functional separation of the inner cell mass from the trophectoderm (TE) is a special feature of mammalian development and is the first cell lineage specification in these embryos. Following fertilization in the oviduct, the mammalian embryo undergoes a relatively slow round of
444:
Blastomeres isolated from the ICM of mammalian embryos and grown in culture are known as embryonic stem (ES) cells. These pluripotent cells, when grown in a carefully coordinated media, can give rise to all three germ layers (ectoderm, endoderm, and mesoderm) of the adult body. For example, the
435:
Although this dichotomy of genetic interactions is clearly required to divide the blastomeres of the mouse embryo into both the ICM and TE identities, the initiation of these feedback loops remains under debate. Whether they are established stochastically or through an even earlier asymmetry is
279:
Since segregation of pluripotent cells of the inner cell mass from the remainder of the blastocyst is integral to mammalian development, considerable research has been performed to elucidate the corresponding cellular and molecular mechanisms of this process. There is primary interest in which
291:
Early embryo apical and basolateral polarization is established at the 8-16 cell stage following compaction. This initial difference in environment strengthens a transcriptional feedback loop in either an internal or external direction. Inside cells express high levels of
390:
may help to upregulate Cdx2 in the TE and its transcriptional activity depends on the coactivator Yap. Yap's nuclear localization in outside cells allows it to contribute to TE specificity, whereas inside cells sequester Yap in the cytoplasm through a phosphorylation
602:
Suwinska A, Czołowska R, Ozdze_nski W, Tarkowski AK. 2008. Blastomeres of the mouse embryo lose totipotency after the fifth cleavage division: Expression of Cdx2 and Oct4 and developmental potential of inner and outer blastomeres of 16- and 32-cell embryos. Dev Biol
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Bischoff, Marcus, et al. Formation of the embryonic-abembryonic axis of the mouse blastocyst: relationships between orientation of early cleavage divisions and pattern of symmetric/asymmetric divisions. Development 135, 953-962
254:. Each cell of the morula, called a blastomere, increases surface contact with its neighbors in a process called compaction. This results in a polarization of the cells within the morula, and further cleavage yields a
676:
Strumpf D, Mao CA, Yamanaka Y, Ralston A, Chawengsaksophak K, Beck F, Rossant J. 2005. Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development
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Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Sch€oler H, Smith A. 1998. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell
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At the transcription level, the transcription factors Oct4, Nanog, Cdx2, and Tead4 have all been implicated in establishing and reinforcing the specification of the ICM and the TE in early mouse embryos.
445:
transcription factor LIF4 is required for mouse ES cells to be maintained in vitro. Blastomeres are dissociated from an isolated ICM in an early blastocyst, and their transcriptional code governed by
404:, which upregulates its own expression through a downstream transcription factor, Elf5. In concert with a third transcription factor, Eomes, these genes act to suppress pluripotency genes like
739:
Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M and Rogers D (1988) Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature, 336, 688–690
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Jedrusik, Agnieszka, et al. Role of Cdx2 and cell polarity in cell allocation and specification of trophectoderm and inner cell mass in the mouse embryo. Genes Dev. 2008 22: 2692-2706
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Nishioka N, et al. 2009. The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell 16: 398–410.
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Robertson, Elizabeth , et al. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector. Nature 323, 445 – 448 (2 October 1986)
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Marikawa, Yusuke, et al. Establishment of
Trophectoderm and Inner Cell Mass Lineages in the Mouse Embryo. Molecular Reproduction & Development 76:1019–1032 (2009)
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genetic knockout cells both in vivo and in culture display TE morphological characteristics. It has been shown that one transcriptional target of Oct4 is the
386:-null embryos, the Tead4-null embryos can yield embryonic stem cells, indicating that Tead4 is dispensable for ICM specification. Recent work has shown that
317:
is expressed in the ICM and participate in maintaining its pluripotency, a role that has been recapitulated in ICM derived mouse embryonic stem cells.
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Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P. 2005. Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem 280:24731–24737.
259:
as 9-15 cells and in rabbits not until after 32 cells. There is also interspecies variation in gene expression patterns in early embryos.
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One benefit to the regulative nature in which mammalian embryos develop is the manipulation of blastomeres of the ICM to generate
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gene. This gene normally encodes a ligand secreted by the ICM, which induces proliferation in the adjacent polar TE.
412:
in the outside cells. Thus, TE becomes specified and differentiates. Inside cells, however, do not turn on the
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gene undergo compaction, but lose the TE epithelial integrity during the late blastocyst stage. Furthermore,
152:
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Validation of reference genes for quantitative RT-PCR studies in porcine oocytes and preimplantation embryos
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and the inside cells maintain pluripotency generate the ICM and eventually the rest of the embryo proper.
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is strongly expressed in the TE and is required for maintaining its specification. Knockout mice for the
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is required for specification of trophectoderm in pre-implantation mouse embryos. Mech Dev 125:270–283.
340:-null mice do not show the reversion of the ICM to a TE-like morphology, but demonstrate that loss of
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expression is subsequently raised in these TE cells, indicating Cdx2 plays a role in suppressing
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is also expressed in the ICM and participates in maintaining its pluripotency. In contrast with
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is required for TE function, although the transcription factor is expressed ubiquitously.
382:-null mice similarly undergo compaction, but fail to generate the blastocoel cavity. Like
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Nishioka N, Yamamoto S, Kiyonari H, Sato H, Sawada A, Ota M, Nakao K, Sasaki H. 2008.
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will give rise to the ultimate embryo proper as well as some extraembryonic tissues.
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Analysis of
Polarity of Bovine and Rabbit Embryos by Scanning Electron Microscopy
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in this cell lineage. Moreover, embryonic stem cells can be generated from
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367:-null mice, demonstrating that Cdx2 is not essential for ICM specification.
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that will eventually give rise to the definitive structures of the
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BMC Developmental
Biology 2007, 7:58 doi:10.1186/1471-213X-7-58
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embryoblastus; massa cellularis interna; pluriblastus senior
229:. The ICM is entirely surrounded by the single layer of
559:(3rd ed.). New York: Oxford University Press Inc.
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213:. The inner cell mass forms in the earliest stages of
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prevents the ICM from generating primitive endoderm.
395:Together these transcription factors function in a
27:Early embryonic mass that gives rise to the fetus
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267:contributes to extraembryonic membranes and the
201:) is a structure in the early development of an
304:which causes TE differentiation and suppresses
146:cell mass_by_E6.0.1.1.2.0.4 E6.0.1.1.2.0.4
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481:Blastodermic vesicle of Vespertilio murinus.
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296:which maintains pluripotency and suppresses
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626:Biol of Reproduction, 50, 163-170 1994
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205:. It is the mass of cells inside the
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275:Regulation of cellular specification
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530:Developmental Biology. 6th edition
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416:gene, and express high levels of
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526:"Early Mammalian Development"
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1058:Somatopleuric mesenchyme
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428:. These genes suppress
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165:Anatomical terminology
1085:Developmental biology
1048:Intraembryonic coelom
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215:embryonic development
241:Further development
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468:Additional images
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892:Germ layers
842:Trophoblast
655:95:379–391.
223:endometrium
191:embryoblast
111:Identifiers
51:trophoblast
18:Embryoblast
1031:Somitomere
918:Blastopore
882:Trilaminar
832:Blastocyst
827:Blastocoel
822:Cavitation
812:Blastomere
511:References
440:Stem cells
256:blastocyst
207:blastocyst
199:marsupials
195:pluriblast
89:Blastocyst
47:Blastocyst
864:Hypoblast
855:Bilaminar
265:hypoblast
248:cleavages
221:into the
217:, before
105:hypoblast
84:Precursor
1079:Category
1021:Paraxial
1008:Mesoderm
990:Endoderm
952:Ectoderm
930:Gastrula
869:Epiblast
807:Cleavage
620:Archived
499:See also
328:Nanog:
269:epiblast
101:Epiblast
878:Week 3
851:Week 2
635:Kuijk,
612:Koyama
233:of the
225:of the
134:D053624
58:Details
1026:Somite
817:Morula
802:Zygote
785:Week 1
709:(2008)
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535:13 May
453:, and
424:, and
391:event.
347:Cdx2:
313:Oct4:
252:morula
227:uterus
203:embryo
688:Tead4
637:et al
614:et al
455:Nanog
422:Nanog
410:Nanog
388:Tead4
380:Tead4
376:Tead4
342:Nanog
338:Nanog
330:Nanog
211:fetus
189:) or
169:[
158:86557
117:Latin
561:ISBN
537:2022
451:Sox2
447:Oct4
430:Cdx2
426:Sox2
418:Oct4
414:Cdx2
408:and
406:Oct4
402:Cdx2
384:Cdx2
372:Cdx2
365:Cdx2
361:Oct4
357:Oct4
353:Cdx2
349:Cdx2
334:Oct4
323:Fgf4
319:Oct4
315:Oct4
306:Oct4
302:Cdx2
298:Cdx2
294:Oct4
181:The
129:MeSH
75:Days
197:in
187:ICM
153:FMA
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