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Patterning of the embryo: the first spatial decisions in the life of a mouse

Wellcome/CRC Institute and Department of Genetics, Tennis Court Road, Cambridge CB2 1QR, UK

View larger version (91K): [in a new window]   Fig. 1. Pre-implantation development of the mouse embryo from the zygote to the blastocyst stage. (A) Fertilised egg with visible female (pink star) and male (blue star) pronuclei and polar body marking the animal pole (red asterisk). (B) Two-cell stage embryo. (C) Eight-cell stage embryo. (D) Early blastocyst showing its animal-vegetal (yellow) and embryonic-abembryonic (blue) axes. (E-G) Expanding blastocyst seen from three different perspectives to show its bilateral symmetry. (E) View from the side, focused on plane of bilateral symmetry to show the long axis (yellow) of the ICM. (F) View from the animal pole to show the short axis (green) of the ICM. (G) View from the embryonic pole to show both long and short axes of the ICM. Scale bar: 25 µm.

View larger version (56K): [in a new window]   Fig. 2. Relationship between lineages of the pre-implantation blastocyst and post-implantation egg cylinder with summary showing asymmetric distribution of visceral endoderm cells at E5.5 and E6.5. (A-C) Core of the ICM in the blastocyst (A, blue) contributes to the epiblast of the egg cylinder at E5.5 (B) and E6.5 (C). Primitive endoderm in the blastocyst (A, yellow) contributes to parietal endoderm (not shown) and visceral endoderm of the egg cylinder (B,C). Polar trophectoderm (A, green) develops into extra-embryonic ectoderm of the egg cylinder (B,C). Colour has been added to DIC images of embryos to indicate lineage relationships between cells. (D) Schematic representation (box-whisker plots) of findings of Weber et al. (Weber et al., 1999) tracing the fate of ICM cells near the polar body (as indicated by the green star) (N/PB, blue) and away from it (A/PB, red) during development from blastocyst to egg cylinder stages. Bar indicates median; the lower and upper limit of the boxes and their whiskers illustrate 25%, 75% and entire range of distributions, respectively. N/PB descendants in visceral endoderm tend to be distributed more distally (embryonic), and A/PB descendants are distributed more proximally (extra-embryonic). This reciprocal fate of visceral endoderm descendants is already apparent at E5.5 and accentuates with development to E6.5.

View larger version (45K): [in a new window]   Fig. 3. Schematic model based on Smith’s observations and conclusions on relationship between asymmetry of the blastocyst and early post-implantation egg cylinder (Smith, 1980; Smith 1985; Gardner et al., 1992) and further modified to emphasise unresolved issues. (A) Implanting blastocyst oriented with its embryonic-abembryonic axis parallel to the mesometrial-antimesometrial axis of the uterus. Smith observed the upward tilting of the polar trophectoderm-ICM complex and thus assigned the blastocyst an anteroposterior axis. (B) Post-implantation egg cylinder showing corresponding asymmetries including tilting of the ectoplacental cone. The relationships between the tilt in the blastocyst, the tilt in the ectoplacental cone of the egg cylinder and the polarity of the anteroposterior axis, are still unsettled. A, anterior; Ab, abembryonic; Em, embryonic; P, posterior.

View larger version (112K): [in a new window]   Fig. 4. Distribution of GFP-labelled descendants in the visceral endoderm of post-implantation egg cylinder at E6.5. Blastocyst was labelled with GFP mRNA in an A/PB cell, then examined at early gastrula stage by confocal microscopy (flattened z series). Clones in the extra-embryonic region are coherent, while in the embryonic region they tend to become dispersed. Distribution of visceral endoderm cells reflects characteristic cell displacements (reminiscent of polonaise movements), which are hypothesised to ‘draw’ anterior extra-embryonic cells towards the posterior midline, and spread them along both left and right sides of the embryo. Although similar movements are postulated to occur on both sides of the embryonic part of the egg cylinder, the distribution of labelled cells is not entirely symmetrical, as indicated by differences in clone shapes and the locations of labelled cells on left versus right sides of the egg cylinder. Anterior on the left in the left hand panel

View larger version (31K): [in a new window]   Fig. 5. Model of visceral endoderm cell movements and accompanying changes in gene expression patterns associated with the anteroposterior axis formation between E5.5 and E6.5 [based on data from Beddington and Robertson (Beddington and Robertson, 1999) and Kimura et al. (Kimura et al., 2001)]. Visceral endoderm (specifically distal and later AVE, expressing Hex and Cer-like, in red) and extra-embryonic ectoderm (specifically distal, expressing BMP4, orange arrows) are implicated in axis definition in the adjacent epiblast. Axis specification involves anterior movement of the visceral endoderm (red arrow) from the distal tip of the egg cylinder and the posterior shift (white arrow) of gene expression (for example, brachyury and Wnt3) from the initially proximal epiblast towards the posterior by E6.25 (in turquoise). The anterior displacement of the visceral endoderm cells is proposed to be important in shifting the expression of genes in the proximal epiblast towards the posterior by inhibiting their expression in the future anterior. White ‘T’ arrows represent putative posterior repressing activity [demonstrated at E6.5 (Kimura et al., 2000), but still hypothetical for earlier stages].

View larger version (68K): [in a new window]   Fig. 6. Distinguishable fates of blastomeres of the two-cell embryo. Confocal sections of a blastocyst showing that the clonal border between progeny of the two-cell blastomeres corresponds with a plane separating the embryonic and abembryonic parts. Blastomeres were labelled at the two-cell stage with dyes of different colours (Piotrowska et al., 2001). The boundary zone is marked with broken red lines and the border of the blastocoel was traced on a central section and is shown projected onto each of the other sections as a broken white line. (A-H) Individual optical sections at 7.5 µm intervals in the ‘z-dimension’. There is a tilt of the clonal border that can be seen in the ‘z-dimension’ of this series of micrographs. Scale bar: 20 µm.

View larger version (42K): [in a new window]   Fig. 7. The embryonic part of the blastocyst tends to be derived from the first blastomere to divide at the two-cell stage. (A) Egg shortly after fertilisation showing the fertilisation cone (fc) with sperm tail coloured in yellow and fluorescent bead marking the sperm entry point (SEP) shown in green. Second polar body marks the animal pole. The first cleavage plane, which is marked by both the polar body and the SEP, divides the zygote into two cells (B, ‘red and blue’) that follow distinguishable fates. In the three-cell embryo (C), the blastomere that inherits the SEP (red) tends to divide first to produce cells that populate predominantly the embryonic part of the blastocyst. The first cleavage plane is reflected in the blastocyst (D) as the border between the lineages comprising the embryonic part (ICM destined to become epiblast and overlying polar trophectoderm, shown in red) and the lineages of the abembryonic part (ICM cells that are located more towards the blastocoel – thus tending to develop into primitive endoderm and mural trophectoderm, shown in blue). Blastocyst shown in a comparable orientation to the embryos in B,C to indicate its two major axes: animal-vegetal and embryonic-abembryonic. For illustration, colour has been added to DIC images of embryos to indicate lineage relationships between cells. Scale bar: 20 µm.

View larger version (39K): [in a new window]   Fig. 8. Decision-making in the early mouse embryo. The prevailing models (upper panels) over the past 20-30 years have acknowledged a differentiation event that discriminates ICM (white) from trophectoderm (pale green) lineages. In the ‘inside-outside’ hypothesis Tarkowski and Wroblewska (Tarkowski and Wroblewska, 1967) proposed that the daughter cells that are directed inwards upon the 4th cell division (8- to 16-cell stage) encounter an environment that leads them to become ICM. However, in the ‘polarisation’ hypothesis, Johnson and Ziomek (Johnson and Ziomek, 1981) argued that blastomeres are polarised at the eight-cell stage, so the 4th and subsequent divisions can generate daughters with different cytoplasmic and cortical components, hence differing fates. The ‘cleavage-driven’ hypothesis incorporates elements of these earlier models for formation of the ICM and the trophectoderm, but recognises the novel findings that the first cleavage divides the embryo into its future embryonic (red) and abembryonic (blue) parts. The progeny of the two-cell blastomere that has a division advantage at the second cleavage tend to occupy the embryonic part, while the progeny of the later dividing blastomere tend to occupy the abembryonic part of the blastocyst. The blastocyst cavity is often slightly tilted from the embryonic-abembryonic clonal border. This ‘cleavage-driven’ hypothesis proposes that blastocyst polarity arises from asymmetries that are generated during early cleavage of the embryo. Thus, it predicts that either composition or behaviour of blastomeres differ along the future axes of the embryo, resulting in the overall polarised form of the blastocyst.

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