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SCIENCE & ANIMALS: The mouse is not enough to study mammalian embryogenesis



                                  PART 1


------------------------------- GENET-news -------------------------------

TITLE:   THE MOUSE IS NOT ENOUGH

SOURCE:  The Scientist, USA

AUTHOR:  Hannah Waters

URL:     http://www.the-scientist.com/news/display/57986/

DATE:    14.02.2011

SUMMARY: "the mechanism of cell commitment in early embryos differs between mice and cows, suggesting that development in mice may not be representative of development in other mammals, including humans. This research suggests "that the mouse alone is not the ideal model if you want to study mammalian embryogenesis," said Michael Bader, a cardiovascular biologist who works on rat embryogenesis at the Max Delbruck Center for Molecular Medicine in Berlin and was not involved in the research."

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THE MOUSE IS NOT ENOUGH

Early embryonic development differs between mice and cows, suggesting mice may not reflect mammalian development as well as scientists had believed

Traditionally studied lab mice may not be the best model for understanding early embryonic development, according to new research published today (February 14) in Developmental Cell.

Specifically, the mechanism of cell commitment in early embryos differs between mice and cows, suggesting that development in mice may not be representative of development in other mammals, including humans.

This research suggests "that the mouse alone is not the ideal model if you want to study mammalian embryogenesis," said Michael Bader, a cardiovascular biologist who works on rat embryogenesis at the Max Delbruck Center for Molecular Medicine in Berlin and was not involved in the research.

"The author should be really commended for dissecting the process of differentiation in the bovine embryo," added Mylene Yao, a fertility specialist who studies early mammalian development at Stanford University, and also did not participate in this study. "It has really great implications for mammalian systems and potentially human development."

After fertilization, the zygote divides to create a blastocyst -- a small mass of cells, all of which are undifferentiated and able to develop into any cell type. The mass then divides into the trophectoderm (TE), which develops into the placenta, and the inner cell mass (ICM), which is fated to become the rest of the organism.

As the cells commit to these two types, they become unable to modify their fates, even when moved to a new context. In the mouse, this commitment involves a balance of two transcription factors, Cdx2 and Oct4. In the late blastocyst stage in mice, Cdx2 becomes localized in the TE while Oct4, a signal of pluripotency in stem cells, is expressed only in the ICM.

But in cows, it turns out, Oct4 is expressed throughout the blastocyst, including in the TE cells, until far later in development. Paper author Peter Pfeffer, a developmental biologist at the AgResearch Crown Research Institute in New Zealand, noticed the peculiar expression pattern during his research on cattle embryo development.

While some differences may be expected between mouse and cow development, it was unexpected to find that "something as fundamental as the stem cell factor Oct4 is actually quite differentially expressed in the earliest lineage," Pfeffer said.

Upon further investigation, Pfeffer and his team identified a region of the Oct4 gene, called CR4, that mediates its breakdown. Sure enough, when the researchers created a transgenic mouse that expressed the bovine CR4 region, they saw the more widespread Oct4 expression that they had observed in cattle.

The differences in Oct4 expression may be symptomatic of more widespread anomalies in early mouse development, said Pfeffer. In most mammals, the embryo floats freely around the uterus for a week before it implants, he explained, but mouse embryos implant very quickly -- and thus the embryos require their placenta for sustenance much earlier. "The mouse is the outlier, in a way... [with its] peculiar way of early development," he said.

This study highlights the need to study development in multiple organisms, Richard Behringer, who studies mammalian embryogenesis at the MD Anderson Cancer Center in Texas and was not involved in the research, said in an email. "There is no 'correct' system. Each species is unique and uses its own tailored mechanisms to achieve development. By only studying one species (eg, the mouse), naive scientists believe that it represents all mammals."

Berg, D.K., et al. "Trophectoderm lineage determination in cattle." Developmental Cell 20, 2: 244-55. DOI: 10.1016/j.devcel.2011.01.003



                                  PART 2

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TITLE:   RUAKURA CATTLE EMBRYO RESEARCH RAISES GLOBAL INTEREST

SOURCE:  The New Zealand Herald, New Zealand

AUTHOR:  Geoff Cumming

URL:     http://www.nzherald.co.nz/agriculture/news/article.cfm?c_id=16&objectid=10707331

DATE:    19.02.2011

SUMMARY: "Ruakura scientists are making international waves with research suggesting that cattle embryos may be more useful than mice for understanding early human development. [...] A 5-year AgResearch study in which cattle and mouse embryos were genetically manipulated claims to ?prove for the first time that research using rats and mice may not be able to be reliably extrapolated to apply to large mammals, including cows and humans?."

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RUAKURA CATTLE EMBRYO RESEARCH RAISES GLOBAL INTEREST

Ruakura scientists are making international waves with research suggesting that cattle embryos may be more useful than mice for understanding early human development.

But sadly for mice, they are likely to remain the first resort of scientists researching the first stages of mammal pregnancies.

A 5-year AgResearch study in which cattle and mouse embryos were genetically manipulated claims to ?prove for the first time that research using rats and mice may not be able to be reliably extrapolated to apply to large mammals, including cows and humans?.

The findings - part of work to reduce early embryo loss in dairy herds - focused on a particular gene, Oct 4, which has a role in embryo formation, and found differences in the way it is regulated in mice and cows.

AgResearch embryologist Dr Peter Pfeffer says the use of cow embryos that can be genetically manipulated gives scientists a second model to improve understanding of early pregnancies.

?In terms of embryonic stem cell identity, we think cattle will be more representative than mice of humans.

?By having two mammalian systems we are beginning to understand, we can see that what is common to the mouse and cattle is likely to apply to humans and things that are different may not also apply to humans.?

The study was published this week as the feature article in US journal Developmental Cell and was quickly picked up by online magazine Science.

Under the headline ?The mouse is not enough?, Science quoted Stanford University fertility specialist Mylene Yao, who commended the authors for ?dissecting the process of differentiation in the bovine embryo?.

?It has really great implications for mammalian systems and potentially human development.?

Dr Debra Berg was lead author of the study which needed ERMA approval and construction of a special containment shed.

Early mortality is a growing problem in the dairy industry and Dr Pfeffer says the study shows the need to focus on understanding early embryo development in cattle rather than mice to address the issue.

Dr Pfeffer says it has wider medical implications. ?It?s early days but at least we?ve given a clear example of where cattle are actually more similar to humans [than mice] and thus would be a better model system.?

Associate Professor Mike Legge, of Otago University?s departments of biochemistry and pathology, says significant differences in embryo formation between mammals have been recognised for some time but the research has advanced knowledge of how embryos develop.

?The paper adds to our knowledge of the control of early embryo cell decision-making when critical cell commitment is being made between the placenta and the embryo.?

Legge says there will always be limitations in extending embryo development data to another species.



                                  PART 3

------------------------------- GENET-news -------------------------------

TITLE:   STUDY SHOWS MICE AND RATS NOT BEST RESEARCH MODEL FOR LARGE MAMMAL STUDIES

SOURCE:  AgResearch, New Zealand

AUTHOR:  Press Release

URL:     http://www.agresearch.co.nz/news/pages/news-item.aspx?News-id=11-02-11-1

DATE:    11.02.2011

SUMMARY: "In a study just published, it has been proved for the first time that research using rats and mice may not be able to be reliably extrapolated to apply to large mammals, including cows and humans. [...] ?Our results are significant for New Zealand farmers in particular,? says Dr Pfeffer. ?For instance, to improve the fertility of cows our study shows the cow is best to use as the model for research studies, not mice or rats.?"

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STUDY SHOWS MICE AND RATS NOT BEST RESEARCH MODEL FOR LARGE MAMMAL STUDIES

In a study just published, it has been proved for the first time that research using rats and mice may not be able to be reliably extrapolated to apply to large mammals, including cows and humans.

AgResearch?s Dr Peter Pfeffer and his Ruakura team have had their study and its results featured in the February 14 issue of the prestigious journal Developmental Cell published by Cell Press.

?Our results are significant for New Zealand farmers in particular,? says Dr Pfeffer. ?For instance, to improve the fertility of cows our study shows the cow is best to use as the model for research studies, not mice or rats.?

It identifies important differences in the timing of cell fate commitment during development of mouse and cattle embryos with fundamental implications for generating embryonic stem (?ES?) cells and understanding embryo development.

?Mice are the universal mammalian embryological model system on which most of our knowledge is based and we tacitly assume we can apply this knowledge to humans and livestock. We were therefore intrigued by observations that in mammals such as humans, cattle, pigs and rabbits the key stem gene Oct4 was not shut down in the placental progenitor (?TE?) cells of early embryos,? explains Dr Pfeffer. ?This suggested to us that the mouse is not very representative of other mammals right from the first lineage decision. We therefore decided to develop cattle as a new functional mammalian developmental model system. However, adapting molecular tools commonly used in the mouse to cattle was not only technically demanding but also required overcoming hurdles set by regulatory authorities.?

The Ruakura team, funded by the New Zealand Foundation for Research, Science and Technology and a Royal Society Marsden Grant, discovered that cattle TE cells were committed much later than mouse cells, with Oct4 expression levels remaining strong. In reciprocal transgenic experiments where cattle genes were expressed in the mouse (and vice versa), they demonstrated evolutionary changes in the regulation of Oct4.

?Cattle, ?in contrast to mice - did not repress Oct4 in the TE. Furthermore, somewhat ironically, our studies in cattle led to new insight into Oct4 regulation in the mouse with the discovery that only mice contain functional AP2-factor binding sites necessary for repression of Oct4,? explains Dr Pfeffer. ?Such fundamental evolutionary differences in the regulation of the key stem cell gene Oct4 have wide spread implications in that they may explain the difficulty in ES cell derivation in mammals such as humans and cattle.?

The authors speculate on the evolution of the observed differences, suggesting that because Oct4 expression in mice differs from other mammals, the regulatory circuitry underlying the switch to TE identity has been rewired specifically in mice because the mouse embryo implants in the uterus at an earlier developmental stage than other mammals, therefore requiring earlier TE differentiation.

?We aim to improve embryo health in dairy cattle where embryo mortality has been on the rise over the last two decades. To achieve this goal we need to better understand embryogenesis in this species. Establishing cattle as a new mammalian embryological system that can be genetically manipulated not only has brought us a good step closer to our goal but has challenged notions that mice are representative of either the earliest stages of mammalian development or of embryonic stem cell biology,? concludes Dr. Pfeffer.