ReviewFrom fertilization to gastrulation: axis formation in the mouse embryo
Introduction
The establishment of the anterior–posterior (A-P) axis signals the first overt manifestation of the mature body plan of the mouse embryo. Here we outline recent progress in understanding axis development in the mouse, including evidence that the blueprint for A-P patterning may be laid down at fertilization. We will consider new evidence for the translation of early polarity in the blastocyst into proximal–distal (P-D) polarity (see Fig. 1 legend) in the egg cylinder, and how recent experiments support a model in which P-D polarity is converted into the A-P axis. Finally, we will discuss new information regarding the roles that the visceral endoderm (VE) and anterior definitive endoderm (ADE) play in patterning the A-P axis.
Section snippets
Polarity in the fertilized egg
Does early polarity in the mouse embryo relate to the later A-P axis? In organisms such as Xenopus laevis and Caenorhabditis elegans, the segregation of cytoplasmic determinants within the egg or zygote seems to have a critical role in establishing polarity, and experimental disruption of this early organization can prevent development into a normal embryo 1., 2.. In contrast, the early development of the mouse embryo is highly regulative and refractory to many different experimental
Blastocyst polarity can be traced back to the sperm entry position in the fertilized egg
Previous work has demonstrated that the second polar body usually ends up at the medial region of the embryonic–abembryonic axis of the blastocyst and aligns with the bilateral axis [4] (see Fig. 1 legend). Recently, the injection of green fluorescent protein mRNA into individual blastomeres has indicated that blastomeres at the eight-cell stage retain their position relative to the polar body up until the blastocyst stage [5•]. This suggests that patterning at the eight-cell stage informs
Cell fate allocation in the blastocyst
The means by which cells are allocated to either embryonic or extraembryonic lineages in the blastocyst (Fig. 2) is not understood; however, the early establishment of cell fate may be regulated in part by the POU transcription factor Pou5f1 (also known as Oct4). Pou5f1 is expressed in all blastomeres at the four-cell stage but is downregulated in the trophectoderm by the blastocyst stage [7]. Its expression is maintained in the ICM, with highest protein concentrations accumulating in the
P-D polarity of the extraembryonic ectoderm leads to induction of posterior genes in the proximal epiblast
In addition to the VE, the extraembryonic ectoderm, which is derived from the trophectoderm of the blastocyst (Fig. 2) and is positioned just above the epiblast in the early post-implantation embryo, is important for embryonic patterning. Transplantation experiments in which distal epiblast cells grafted to the proximal epiblast give rise to primordial germ cells and extraembryonic mesoderm — cell types that normally arise from the proximal epiblast — suggest that signaling from the
Cell movements convert P-D polarity to A-P polarity in the egg cylinder as the AVE suppresses posterior fate in adjacent epiblast
Whereas the extraembryonic ectoderm seems to signal to the proximal epiblast to induce expression of proximal–posterior genes, the anterior visceral endoderm (AVE) has been proposed to counter this activity by repressing expression of these genes in the underlying epiblast as it moves anteriorward [18]. It was previously shown that a distinct subpopulation of VE cells at the distal tip of the egg cylinder expressing the homeobox gene Hex moves proximally to mark the prospective anterior side of
Mesoderm induction in the posterior epiblast is independent of AVE patterning
As AVE patterning precedes primitive streak formation, streak formation should not affect AVE patterning. Indeed, recent work has confirmed that AVE patterning occurs independently of primitive streak formation. Wnt3 is expressed in the proximal epiblast and the adjacent proximal VE at the egg cylinder stage (Fig. 3), and subsequently becomes restricted to the posterior epiblast and VE coincident with AVE movement [29•]. Wnt3 mutants express AVE markers such as Lhx1 and Cerl, but fail to
A possible role for the VE in patterning the posterior epiblast
The VE plays a crucial role in anterior development, and recent data provide hints that it may also be important in patterning the posterior of the embryo. As mentioned above, Wnt3 expression initially in the proximal epiblast and VE at the egg cylinder stage becomes restricted to posterior epiblast and VE just before gastrulation (Fig. 3) [29•]. In addition, explant culture experiments have shown that early streak stage VE can cause anterior ectoderm to differentiate into hematopoietic cells,
The anterior primitive streak gives rise to the ADE, which patterns the anterior neurectoderm
Although the AVE appears to repress posterior signals in the epiblast, it is unable to pattern the neurectoderm or cause formation of anterior embryonic structures. The node, which forms at the anterior primitive streak at late gastrula stages, is a classical ‘organizer’, which is capable of inducing a secondary trunk axis in transplantation experiments [33]. Like the AVE, however, it is unable to induce secondary anterior structures even when node precursor cells are transplanted from an early
Conclusions
Rapid progress has been made in unraveling the cellular and molecular basis of early axis patterning; however, much remains to be learned. It will be important to understand how the sperm entry point is linked to embryonic polarity. It is possible that local cytoskeletal reorganization of the actin cortex is responsible — perhaps through the localized uncapping of barbed ends of actin filaments, which stimulates actin polymerization and membrane protrusion. The positioning of the mitotic
Update
A new paper [49], published in the same issue of Genes and Development as [40], further characterizes the Foxh1/2 mutant.
Acknowledgements
We would like to thank the many people who generously sent us preprints of their work or shared unpublished findings. Thanks to Ray Dunn, Dominic Norris and Daniel Constam for discussion and comments on the manuscript. This work was funded by the NIH and supported by a postdoctoral fellowship from the Wellcome Trust (JB).
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
•of special interest
••of outstanding interest
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