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First published online February 6, 2009
doi: 10.1242/10.1242/dev.017178

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Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse

¹ Research Institute, The Hospital for Sick Children and Departments of Molecular Genetics, and Obstetrics and Gynecology, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
² Embryology Unit, Children's Medical Research Institute and Faculty of Medicine, University of Sydney, Locked Bag 23, Wentworthville, NSW 2145, Australia.

View larger version (55K): [in this window] [in a new window]   Fig. 1. Cell lineage formation from egg to egg cylinder. (A-H) Schematics of the morphological changes and cell lineage specification that occur in a mouse embryo, from its fertilization at embryonic day (E) 0.5 to the early egg cylinder stage (E5.5). The colored bars show the progressive allocation of totipotent blastomeres to outer and inner cells and to the trophectoderm and inner cell mass lineages. The cell types in the embryos are color coded. Abemb. Emb., abembryonic-embryonic axis of the blastocyst; DVE, distal visceral endoderm.

View larger version (62K): [in this window] [in a new window]   Fig. 2. Molecular players in the formation of the first lineages in the blastocyst. Four lineage-specific transcription factors, Oct4, Cdx2, Nanog and Gata6, are important for the generation of the first three lineages in the blastocyst. The initial expression of these transcription factors is not restricted to specific cell populations. Lineage-specific expression is gradually established in association with the maturation of cellular structures (such as apical-basolateral cell membrane domains, intercellular junctions, etc.) and of positive and negative interactions among the transcription factors themselves. (A) Oct4: Oct4 protein is observed in all blastomeres throughout early cleavage stages due to maternally encoded protein. At the eight-cell stage, all blastomeres contain Oct4. At the blastocyst stage, Oct4 is gradually downregulated in the outer trophectoderm (TE) cells by Cdx2 through direct physical interaction and transcriptional regulation. (B) Cdx2: Cdx2 protein is detected beginning at the eight- to 16-cell stage, its initial expression appears to be stochastic. By the early morula to early blastocyst stages, Cdx2 expression is ubiquitous but higher in outer, apically polarized cells. Restricted expression in outer TE cells is established by the blastocyst stage. (C) Nanog and (D) Gata6: Nanog and Gata6 are detected from the eight-cell stage. Both proteins are expressed uniformly in all cells until the early blastocyst stage. Nanog expression is downregulated in outer cells by Cdx2 and in a subpopulation of the ICM by Grb2-dependent signaling. By contrast, Gata6 expression is maintained by Grb2-dependent signaling. By the late blastocyst stage, ICM cells express either Nanog or Gata6 exclusively.

View larger version (56K): [in this window] [in a new window]   Fig. 3. The relationships among zona pellucida shape, orientation of the two-cell embryo and the embryonic-abembryonic axis of the mouse blastocyst. (A) In many mouse embryos, the zona pellucida is not a sphere, but a scalene ellipsoid. It has three unequal diameters: long (marked by blue arrows and triangles), medium (orange arrows and stars) and short (green arrows and circles). The two-cell stage embryo always aligns its orientation along the long axes in the zona pellucida. The broken double lines show differences in the space between the surface of the blastomere and the zona viewed at two different optical planes: left, view in the optical plane of the long and middle diameters (xy plane in E); right, view in the optical plane of the long and short diameters (yz plane in E). (B-D) With reference to the coordinates of the zona pellucida delineated at the two-cell stage, the abembryonic-embryonic axis in the blastocyst most frequently aligns with the longest diameter of the zona (B) and rarely with the two shorter diameters (C,D). (E,F) The two-cell embryo is visualized in 3D space with the plane of two-cell boundary (P2CB) aligned with the yz plane, the plane of the middle and short diameters of the zona pellucida (each blastomere and its progeny are colored green or orange). (G,H) If the embryo does not rotate during cleavage (or rotates only along the x-axis), this alignment is maintained through (G) the eight-cell to (H) the blastocyst stage. (H) The abembryonic-embryonic axis of the blastocyst forms perpendicularly to the yz plane and the P2CB. The progeny of each two-cell blastomere thus predominantly occupies either the abembryonic or embryonic domain of the blastocyst. This situation occurs in embryos in which cell movement within the zona is limited or prevented by alginate. (I-L) If the embryo rotates within the zona during cleavage, the P2CB will no longer be aligned with the yz plane (I,K). The abembryonic-embryonic axis of the blastocyst still forms perpendicularly to the yz plane, according to the shape of the zona pellucida, but the P2CB does not align with the abembryonic-embryonic axis (J,L). Two hypothetical examples are shown in which an embryo is rotated 90° along the y axis (I) or the z axis (K). In these situations, the progeny of each two-cell blastomere shows no predictable relationship to the lineages of the blastocyst or occupancy of specific domains. In real development, the angle between P2CB and the yz plane is often oriented between I and K; thus, the position of P2CB in blastocysts varies.

View larger version (60K): [in this window] [in a new window]   Fig. 4. The emergence of asymmetry during peri-implantation development from blastocyst to immediately before gastrulation. (A-D) Early pre-gastrulation stages of mouse development, with asymmetric features listed for each stage. The tilting of the ectoplacental cone from the proximal-distal axis (unbroken line) is indicated by the black broken line. Cells in the inner cells mass (ICM), the primitive endoderm and the visceral endoderm that express β-catenin, Lefty1, Cer1 or Wnt3 are color coded. Many genes that are expressed in the anterior visceral endoderm (AVE; D broken green rectangle) are also expressed previously in the distal visceral endoderm (DVE). Four examples of genes that are expressed in the posterior epiblast (D, broken black outline) are listed. In C (embryo with DVE) and D (embryo with AVE), a transverse section of the embryo is shown to illustrate the alignment of the prospective anterior-posterior (AP) axis first with the shorter and then with the longer diameter at the respective stage.

View larger version (49K): [in this window] [in a new window]   Fig. 5. The formation and movement of the distal visceral endoderm. (A) Schematic of a mouse embryo with discernible thickening of the distal part of the visceral endoderm (left), showing the domains of expression of the molecules involved in the formation of the distal visceral endoderm (DVE, marked by the red broken line). (Right) The cascade of molecular activity, which involves Nodal, bone morphogenetic protein (BMP) and WNT signaling in DVE formation and epiblast patterning. Arrows and bar-pointers between genes or molecules indicate positive and negative functional connections in the cascade, respectively, and not necessarily a regulatory relationship. (B) Factors that drive the anterior displacement of the DVE to form the anterior visceral endoderm (AVE). (a) DVE cells may move to the anterior region by active locomotion: unbroken arrows indicate the direction of movement of the DVE, and the broken double-headed arrows show the distribution of inner cell mass-derived clones in the visceral endoderm. DVE movement can also be driven by morphogenetic forces generated by: (b) differential rates of cell proliferation under the influence of Nodal signaling; and (c) graded levels of WNT signaling activity that elicit a chemotactic response. (d) A potential role of localized changes in cell shape and cell intercalation in the displacement of cells in the visceral endoderm, without an increase in cell number or the long-range movement of individual cells within an epithelium. Cell shape changes might be subject to planar signaling activity and mediated by molecular mechanisms that control cytoarchitecture. Lefty1- and Cer1-expressing cells in the visceral endoderm are colored in dark blue and green, respectively.

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