Anatomy of a blastocyst: Cell behaviors driving cell fate choice and morphogenesis in the early mouse embryo

The preimplantation period of mouse early embryonic development is devoted to the specification of two extraembryonic tissues and their spatial segregation from the pluripotent epiblast. During this period two cell fate decisions are made while cells gradually lose their totipotency. The first fate decision involves the segregation of the extraembryonic trophectoderm (TE) lineage from the inner cell mass (ICM); the second occurs within the ICM and involves the segregation of the extraembryonic primitive endoderm (PrE) lineage from the pluripotent epiblast (EPI) lineage, which eventually gives rise to the embryo proper. Multiple determinants, such as differential cellular properties, signaling cues and the activity of transcriptional regulators, influence lineage choice in the early embryo. Here, we provide an overview of our current understanding of the mechanisms governing these cell fate decisions ensuring proper lineage allocation and segregation, while at the same time providing the embryo with an inherent flexibility to adjust when perturbed. genesis 51:219–233. © 2013 Wiley Periodicals, Inc.

[1]  A. Enders,et al.  Differentiation and migration of endoderm in the rat and mouse at implantation , 1978, The Anatomical record.

[2]  Chi-Wei Lu,et al.  Cross-regulation of the Nanog and Cdx2 promoters , 2009, Cell Research.

[3]  V. Papaioannou,et al.  Paracrine action of FGF4 during periimplantation development maintains trophectoderm and primitive endoderm , 2003, Genesis.

[4]  K. Szczepańska,et al.  Delay of polarization event increases the number of Cdx2-positive blastomeres in mouse embryo. , 2012, Developmental biology.

[5]  Ge Guo,et al.  Nanog Is the Gateway to the Pluripotent Ground State , 2009, Cell.

[6]  B. Hogan,et al.  In vitro development of inner cell masses isolated immunosurgically from mouse blastocysts. II. Inner cell masses from 3.5- to 4.0-day p.c. blastocysts. , 1978, Journal of embryology and experimental morphology.

[7]  D. Capco,et al.  Regulation of cell adhesion during embryonic compaction of mammalian embryos: Roles for PKC and β‐catenin , 1999, Molecular reproduction and development.

[8]  J. Rossant,et al.  Potential of isolated mouse inner cell masses to form trophectoderm derivatives in vivo. , 1979, Developmental biology.

[9]  B. Maro,et al.  Inactivation of aPKCλ Reveals a Context Dependent Allocation of Cell Lineages in Preimplantation Mouse Embryos , 2009, PloS one.

[10]  A. Mclaren,et al.  Factors affecting the time of formation of the mouse blastocoele. , 1977, Journal of embryology and experimental morphology.

[11]  M. Elowitz,et al.  Functional roles for noise in genetic circuits , 2010, Nature.

[12]  J. Rossant,et al.  Investigation of the fate of 4-5 day post-coitum mouse inner cell mass cells by blastocyst injection. , 1979, Journal of embryology and experimental morphology.

[13]  Samantha A. Morris,et al.  Developmental Plasticity Is Bound by Pluripotency and the Fgf and Wnt Signaling Pathways , 2012, Cell reports.

[14]  Jun Qin,et al.  Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells , 2008, Nature Cell Biology.

[15]  Tony Pawson,et al.  Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. , 2006, Developmental cell.

[16]  J. Nichols,et al.  Functional Expression Cloning of Nanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells , 2003, Cell.

[17]  Jiaxuan Chen,et al.  Conversion of Sox17 into a Pluripotency Reprogramming Factor by Reengineering Its Association with Oct4 on DNA , 2011, Stem cells.

[18]  Janet Rossant,et al.  The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. , 2009, Developmental cell.

[19]  Tristan Frum,et al.  Maternal Cdx2 is dispensable for mouse development , 2012, Development.

[20]  R. Gardner,et al.  An investigation of the fate of cells transplanted orthotopically between morulae/nascent blastocysts in the mouse. , 1991, Human reproduction.

[21]  Janet Rossant,et al.  Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse , 2009, Development.

[22]  R. Lovell-Badge,et al.  Multipotent cell lineages in early mouse development depend on SOX2 function. , 2003, Genes & development.

[23]  S. Paul,et al.  Reply to Sasaki et al.: TEAD4 is predominantly cytoplasmic in the inner cell mass of mouse blastocysts , 2012, Proceedings of the National Academy of Sciences.

[24]  Janet Rossant,et al.  Cdx2 acts downstream of cell polarization to cell-autonomously promote trophectoderm fate in the early mouse embryo. , 2008, Developmental biology.

[25]  J. Rossant,et al.  Tead4 is constitutively nuclear, while nuclear vs. cytoplasmic Yap distribution is regulated in preimplantation mouse embryos , 2012, Proceedings of the National Academy of Sciences.

[26]  A. Hadjantonakis,et al.  Troika of the mouse blastocyst: lineage segregation and stem cells. , 2012, Current stem cell research & therapy.

[27]  Simon,et al.  Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart , 1993, Molecular and cellular biology.

[28]  J. Bowles,et al.  Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. , 2000, Developmental biology.

[29]  J. Nichols,et al.  Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo , 2009, Development.

[30]  J. Rossant,et al.  Lineage allocation and asymmetries in the early mouse embryo. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[31]  Janet Rossant,et al.  Interaction between Oct3/4 and Cdx2 Determines Trophectoderm Differentiation , 2005, Cell.

[32]  T. Enver,et al.  Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells. , 2005, Human molecular genetics.

[33]  Nicola Festuccia,et al.  OCT4/SOX2‐independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cells , 2012, The EMBO journal.

[34]  Anna-Katerina Hadjantonakis,et al.  Understanding the Molecular Circuitry of Cell Lineage Specification in the Early Mouse Embryo , 2011, Genes.

[35]  V. Alarcon.  Cell Polarity Regulator PARD6B Is Essential for Trophectoderm Formation in the Preimplantation Mouse Embryo1 , 2010, Biology of reproduction.

[36]  Austin G Smith,et al.  Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation , 2012, Nature Cell Biology.

[37]  Zhongmei Zhou,et al.  Tumorigenesis and Neoplastic Progression YAP Promotes Breast Cell Proliferation and Survival Partially through Stabilizing the KLF 5 Transcription Factor , 2012 .

[38]  Kit T. Rodolfa,et al.  Sox17 promotes differentiation in mouse embryonic stem cells by directly regulating extraembryonic gene expression and indirectly antagonizing self-renewal. , 2010, Genes & development.

[39]  J. Nichols,et al.  Nanog safeguards pluripotency and mediates germline development , 2007, Nature.

[40]  H. Schöler,et al.  Formation of Pluripotent Stem Cells in the Mammalian Embryo Depends on the POU Transcription Factor Oct4 , 1998, Cell.

[41]  Shyam Prabhakar,et al.  Deciphering the Sox-Oct partner code by quantitative cooperativity measurements , 2012, Nucleic acids research.

[42]  D. Capco,et al.  The expression and stage-specific localization of protein kinase C isotypes during mouse preimplantation development. , 2000, Developmental biology.

[43]  H. Schöler,et al.  Modulation of the Activity of Multiple Transcriptional Activation Domains by the DNA Binding Domains Mediates the Synergistic Action of Sox2 and Oct-3 on the Fibroblast Growth Factor-4Enhancer* , 2000, The Journal of Biological Chemistry.

[44]  P. Robson,et al.  Transcriptional Regulation of Nanog by OCT4 and SOX2* , 2005, Journal of Biological Chemistry.

[45]  D. Solter,et al.  Immunosurgery of mouse blastocyst. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Chad A. Cowan,et al.  Interplay of Oct4 with Sox2 and Sox17: a molecular switch from stem cell pluripotency to specifying a cardiac fate , 2009, The Journal of cell biology.

[47]  L. Magnani,et al.  Brg1 Is Required for Cdx2-Mediated Repression of Oct4 Expression in Mouse Blastocysts , 2010, PloS one.

[48]  Motoki Saito,et al.  Oct-3/4 and Sox2 Regulate Oct-3/4 Gene in Embryonic Stem Cells* , 2005, Journal of Biological Chemistry.

[49]  Janet Rossant,et al.  Dynamic expression of Lrp2 pathway members reveals progressive epithelial differentiation of primitive endoderm in mouse blastocyst. , 2008, Developmental biology.

[50]  Jennifer Nichols,et al.  Differential plasticity of epiblast and primitive endoderm precursors within the ICM of the early mouse embryo , 2012, Development.

[51]  N. Terada,et al.  A Heterogeneous Expression Pattern for Nanog in Embryonic Stem Cells , 2007, Stem cells.

[52]  M. Murakami,et al.  The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells , 2003, Cell.

[53]  Vachiranee Limviphuvadh,et al.  Developmental fate and lineage commitment of singled mouse blastomeres , 2012, Development.

[54]  Janet Rossant,et al.  Disorganized epithelial polarity and excess trophectoderm cell fate in preimplantation embryos lacking E-cadherin , 2010, Development.

[55]  A. Gould,et al.  Temporal control of neuronal diversity: common regulatory principles in insects and vertebrates? , 2008, Development.

[56]  P. Mangeat,et al.  In vivo functional analysis of ezrin during mouse blastocyst formation. , 2001, Developmental biology.

[57]  Takashi Hiiragi,et al.  Stochastic patterning in the mouse pre-implantation embryo , 2007, Development.

[58]  Janet Rossant,et al.  The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway. , 2010, Developmental cell.

[59]  Julian Gingold,et al.  Zfp281 mediates Nanog autorepression through recruitment of the NuRD complex and inhibits somatic cell reprogramming , 2012, Proceedings of the National Academy of Sciences.

[60]  E. Morrisey,et al.  GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. , 1998, Genes & development.

[61]  J. Heath,et al.  Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[62]  D. Natale,et al.  Establishing Three Blastocyst Lineages—Then What? , 2011, Biology of reproduction.

[63]  Mikael Huss,et al.  Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst. , 2010, Developmental cell.

[64]  J. Dyce,et al.  Do trophectoderm and inner cell mass cells in the mouse blastocyst maintain discrete lineages? , 1987, Development.

[65]  B. Mintz.  Genetic Mosaicism in Adult Mice of Quadriparental Lineage , 1965, Science.

[66]  Samantha A. Morris,et al.  Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo , 2010, Proceedings of the National Academy of Sciences.

[67]  C. Ziomek,et al.  Distribution of microvilli on dissociated blastomeres from mouse embryos: evidence for surface polarization at compaction. , 1981, Journal of embryology and experimental morphology.

[68]  Alexander W. Bruce,et al.  Developmental control of the early mammalian embryo: competition among heterogeneous cells that biases cell fate. , 2010, Current opinion in genetics & development.

[69]  C. Peterson,et al.  Stem cell states, fates, and the rules of attraction. , 2009, Cell stem cell.

[70]  Minjung Kang,et al.  FGF4 is required for lineage restriction and salt-and-pepper distribution of primitive endoderm factors but not their initial expression in the mouse , 2013, Development.

[71]  Alfonso Martinez Arias,et al.  Filtering transcriptional noise during development: concepts and mechanisms , 2006, Nature Reviews Genetics.

[72]  Janet Rossant,et al.  FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst , 2010, Development.

[73]  A. Spindle,et al.  Trophoblast regeneration by inner cell masses isolated from cultured mouse embryos. , 1978, The Journal of experimental zoology.

[74]  N. Hillman,et al.  The effect of spatial arrangement on cell determination during mouse development. , 1972, Journal of embryology and experimental morphology.

[75]  J. Rossant,et al.  Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2 , 2010, Development.

[76]  A. Hadjantonakis,et al.  Cellular dynamics in the early mouse embryo: from axis formation to gastrulation. , 2010, Current opinion in genetics & development.

[77]  T. Pawson,et al.  Asymmetric distribution of PAR proteins in the mouse embryo begins at the 8-cell stage during compaction. , 2005, Developmental biology.

[78]  V. Papaioannou,et al.  Requirement of FGF-4 for postimplantation mouse development , 1995, Science.

[79]  Shinji Yamamoto,et al.  Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos , 2008, Mechanisms of Development.

[80]  P. Mangeat,et al.  Ezrin Becomes Restricted to Outer Cells Following Asymmetrical Division in the Preimplantation Mouse Embryo , 1996 .

[81]  Elizabeth J. Robertson,et al.  Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo , 2009, Nature Reviews Molecular Cell Biology.

[82]  H. Schöler,et al.  Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. , 1994, Developmental biology.

[83]  J. Whitsett,et al.  Klf5 regulates lineage formation in the pre-implantation mouse embryo , 2010, Development.

[84]  Austin G Smith,et al.  Self-renewal of teratocarcinoma and embryonic stem cells , 2004, Oncogene.

[85]  Kazuki Kurimoto,et al.  An improved single-cell cDNA amplification method for efficient high-density oligonucleotide microarray analysis , 2006, Nucleic acids research.

[86]  Joshua M Brickman,et al.  Gene expression heterogeneities in embryonic stem cell populations: origin and function. , 2011, Current opinion in cell biology.

[87]  A. Tarkowski,et al.  Experiments on the Development of Isolated Blastomeres of Mouse Eggs , 1959, Nature.

[88]  J. Rossant,et al.  Mouse embryonic chimeras: tools for studying mammalian development , 2003, Development.

[89]  Anna-Katerina Hadjantonakis,et al.  Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst , 2008, Development.

[90]  Xi Chen,et al.  Reciprocal Transcriptional Regulation of Pou5f1 and Sox2 via the Oct4/Sox2 Complex in Embryonic Stem Cells , 2005, Molecular and Cellular Biology.

[91]  François Gerbe,et al.  Primitive endoderm differentiates via a three-step mechanism involving Nanog and RTK signaling. , 2011, Developmental cell.

[92]  Jarrett Rosenberg,et al.  Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells. , 2011, The Journal of clinical investigation.

[93]  Samantha A. Morris,et al.  Making a firm decision: multifaceted regulation of cell fate in the early mouse embryo , 2009, Nature Reviews Genetics.

[94]  H. Niwa,et al.  Identification and characterization of subpopulations in undifferentiated ES cell culture , 2008, Development.

[95]  C. Ziomek,et al.  Induction of polarity in mouse 8-cell blastomeres: specificity, geometry, and stability , 1981, The Journal of cell biology.

[96]  M. DePamphilis,et al.  Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development , 2007, Development.

[97]  Sean C. Bendall,et al.  Clonal isolation of hESCs reveals heterogeneity within the pluripotent stem cell compartment , 2006, Nature Methods.

[98]  J. Rossant,et al.  Heparan Sulfation–Dependent Fibroblast Growth Factor Signaling Maintains Embryonic Stem Cells Primed for Differentiation in a Heterogeneous State , 2009, Stem cells.

[99]  B. Hogan,et al.  In vitro development of inner cell masses isolated immunosurgically from mouse blastocysts. I. Inner cell masses from 3.5-day p.c. blastocysts incubated for 24 h before immunosurgery. , 1978, Journal of embryology and experimental morphology.

[100]  Stuart H. Orkin,et al.  A protein interaction network for pluripotency of embryonic stem cells , 2006, Nature.

[101]  R. Sherwood,et al.  Conversion from mouse embryonic to extra-embryonic endoderm stem cells reveals distinct differentiation capacities of pluripotent stem cell states , 2012, Development.

[102]  C. Mueller,et al.  GATA-4/5/6, a subfamily of three transcription factors transcribed in developing heart and gut. , 1994, The Journal of biological chemistry.

[103]  Nancy Papalopulu,et al.  Downregulation of Par3 and aPKC function directs cells towards the ICM in the preimplantation mouse embryo , 2005, Journal of Cell Science.

[104]  J. McGhee,et al.  The GATA family (vertebrates and invertebrates). , 2002, Current opinion in genetics & development.

[105]  Janet Rossant,et al.  Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst , 2005, Development.

[106]  H. Schöler,et al.  A family of octamer‐specific proteins present during mouse embryogenesis: evidence for germline‐specific expression of an Oct factor. , 1989, The EMBO journal.

[107]  Anna-Katerina Hadjantonakis,et al.  The primitive endoderm lineage of the mouse blastocyst: sequential transcription factor activation and regulation of differentiation by Sox17. , 2011, Developmental biology.

[108]  Barry Behr,et al.  Altered subcellular localization of transcription factor TEAD4 regulates first mammalian cell lineage commitment , 2012, Proceedings of the National Academy of Sciences.

[109]  Austin G Smith,et al.  Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation , 2011, Nature Cell Biology.

[110]  Guoji Guo,et al.  Role of Cdx2 and cell polarity in cell allocation and specification of trophectoderm and inner cell mass in the mouse embryo. , 2008, Genes & development.

[111]  M. Torres-Padilla,et al.  Control of ground-state pluripotency by allelic regulation of Nanog , 2012, Nature.

[112]  R. Kemler,et al.  Nanog is required for primitive endoderm formation through a non-cell autonomous mechanism. , 2010, Developmental biology.

[113]  Samantha A. Morris,et al.  Active cell movements coupled to positional induction are involved in lineage segregation in the mouse blastocyst. , 2009, Developmental biology.

[114]  A. Tarkowski,et al.  Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage. , 1967, Journal of embryology and experimental morphology.

[115]  Periklis Pantazis,et al.  Oct4 kinetics predict cell lineage patterning in the early mammalian embryo , 2011, Nature Cell Biology.

[116]  A. Handyside.  Time of commitment of inside cells isolated from preimplantation mouse embryos. , 1978, Journal of embryology and experimental morphology.

[117]  C. Lim,et al.  Regulated Fluctuations in Nanog Expression Mediate Cell Fate Decisions in Embryonic Stem Cells , 2009, PLoS biology.

[118]  F. Grosveld,et al.  The transcription factor GATA6 is essential for early extraembryonic development. , 1999, Development.

[119]  A. Hadjantonakis,et al.  The endoderm of the mouse embryo arises by dynamic widespread intercalation of embryonic and extraembryonic lineages. , 2008, Developmental cell.