What the papers say...
February 2011
Proclaiming fate in the early mouse embryo.
Magdalena Zernicka-Goetz
Nature Cell Biology. 2011.
In the mouse embryo, the first differences between cells that result in distinct lineages have long been thought to arise only as a consequence of differential cell positioning at relatively late preimplantation stages. Differences in Oct4 transcription factor kinetics between cells at the 4–8-cell stage are now shown to be predictive of future lineages, providing further evidence for much earlier initiation of cell fate decisions.
December 2010
The chromosome passenger complex is required for fidelity of chromosome transmission and cytokinesis in meiosis of mouse oocytes.
Bedra Sharif, Jie Na, Karin Lykke-Hartmann, Stephen H. McLaughlin, Ernest Laue, David M. Glover, and Magdalena Zernicka-Goetz.
Journal of Cell Science. 2010. Pubmed
A meiotic tale of two Auroras. The chromosome passenger complex (CPC), which contains the serine/thronine kinase Aurora B, the inner centromere protein ICENP, Survivin and Borealin, regulates chromosome segregation and cytokinesis during mitosis. Less is known about CPC's role in female meiosis, partly because mammalian oocytes contain two CPC forms: an Aurora B-containing form and an Aurora C-containing form. Now, by modulating the expression of key CPC components, Magda Zernicka-Goetz Group reveal that CPC is required for faithful chromosome transmission and cytokinesis during mouse oocyte maturation. We show that depletion of INCENP or combined inhibition of Aurora B and C leads to the activation of the anaphase-promoting complex (APC/C) before the chromosomes have correctly aligned and then subsequently prevents cytokinesis. Importantly, however, whereas overexpression of Aurora C has a dominant negative effect on the CPC and advances APC/C activation and prevents cytokinesis, overexpression of Aurora B prevents APC/C activation, stabilises Securin and leads to failure of homologues to separate in meiosis I. Thus, Aurora B and Aurora C have overlapping but partly independent roles in mammalian meiosis.
May 2010
Maternally and zygotically provided Cdx2 have novel and critical roles for early development of the mouse embryo.
Agnieszka Jedrusik, Alexander W. Bruce, Meng H. Tan, Denise E. Leong, Maria Skamagki, Mylene Yao and Magdalena Zernicka-Goetz. Developmental Biology. 2010. Pubmed
Early mouse embryo development is characterised by the emergence of two differentiating extra-embryonic cell lineages, trophectoderm and primitive endoderm (TE and PE respectively), in addition to pluripotent epiblast cells that will give rise to all cells of the developing foetus. Research in the Zernicka-Goetz group has cast new light on how the first of these extra-embryonic lineages, the TE, becomes specified. Working on a gene previously shown in transgenic knock-out models to be essential for embryo viability yet only necessary for the maintenance of a functioning TE, they reveal a hitherto unappreciated and much earlier role for Cdx2 mRNA that is provided maternally from the oocyte. Utilising targeted RNAi and antisense-morpholino mediated approaches to deplete the whole embryo of Cdx2 mRNA (both maternally provided and that derived from subsequent transcription of zygotic alleles) they show that the maternal pool of Cdx2 mRNA is required to progress development beyond the 8-16-cell stage transition. Such Cdx2 depleted embryos fail to compact and cell polarisation cannot be completed. Consequently. the initiation of TE differentiation programme is prevented. The use of such RNAi/morpholino based techniques provides a powerful experimental paradigm when investigating potential maternal effects of key cell fate determining genes that otherwise could not be unmasked by the sole use of conventional zygotic transgeneic knockout approaches. In conclusion, this study reveals two sides to Cdx2 regulation in early development; the first relying on maternally provided Cdx2 to allow appropriate blastomere polarisation and allocation of cells to the presumptive TE compartment and the second reliant on zygotic Cdx2 expression to maintain TE integrity after it’s specification.
March 2010
Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo.
Morris SA, Teo RT, Li H, Robson P, Glover DM, Zernicka-Goetz M. Proc Natl Acad Sci U S A. 2010 Mar 22. Pubmed
A crucial question in mammalian development is how cells of the early embryo differentiate into distinct cell types. The first decision is taken when cells undertake waves of asymmetric division that generate one daughter on the inside and one on the outside of the embryo. After this division, some cells on the inside remain pluripotent and give rise to the epiblast, and hence the future body, whereas others develop into the primitive endoderm, an extraembryonic tissue. How the fate of these inside cells is decided is unknown: Is the process random, or is it related to their developmental origins? To address this question, we traced all cells by live cell imaging in intact, unmanipulated embryos until the epiblast
and primitive endoderm became distinct. This analysis revealed that inner cell mass (ICM) cells have unrestricted developmental potential. However, cells internalized by the first wave of asymmetric divisions are biased toward forming pluripotent epiblast, whereas cells internalized in the next two waves of divisions are strongly biased toward forming primitive endoderm. Moreover, we show that cells internalized by the second wave up-regulate expression of Gata6 and Sox17, and changing the expression of these genes determines whether the cells become primitive endoderm. Finally, with our ability to determine the origin of cells, we find that inside cells that are mispositioned when they are born
can sort into the correct layer. In conclusion, we propose a model in which the timing of cell internalization, cell position, and cell sorting combine to determine distinct lineages of the preimplantation mouse embryo.
Cells generated in the first wave
of asymmetric division are biased to generate EPI and bipotent
precursors, whereas cells generated in the subsequent waves
are biased to generate PE over EPI. Black arrows indicate orientation
of cell division. (c) PE progenitors express Sox17 and
higher levels of Gata6. Most inner cells are positioned according
to their fate when the embryo cavitates in deep or surface
ICM, but some are not. (d) Cells positioned within an inappropriate
layer tend to relocate according to their wave of
origin and fate: PE-destined cells relocate to the surface, and
EPI-destined cells relocate deep. Some cells, particularly in deep
ICM, apoptose. Hypothetically, induction from the cavity might
further enhance PE fate in surface cells. (e) In the mature
blastocyst, PE is fully segregated from EPI.