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

By Hannah Waters | February 14, 2011

Traditionally studied lab mice may not be the best model for understanding early embryonic development, according to new linkurl: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 linkurl: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.
Mouse blastocyst, with the trophectoderm labelled "T" and inner cell mass labelled "I"
Image: Wikimedia commons, User: Ecto
"The author should be really commended for dissecting the process of differentiation in the bovine embryo," added linkurl: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 linkurl: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, linkurl: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: linkurl:10.1016/j.devcel.2011.01.003;
**__Related stories:__***linkurl:One step to human pluripotency;
[28th August 2009]*linkurl:Single-factor stem cells;
[5th February 2009]*linkurl:Model Organisms;
[2nd June 2003]* linkurl:Related F1000 evaluations;
[14th February 2011]


Avatar of: Mike Waldrep

Mike Waldrep

Posts: 155

February 14, 2011

Interesting! I hope that everyone's Sunday was great and I hope that they had a great Abraham Lincoln's birthday and I hope that they are having a great Valentine's Day!
Avatar of: Todd Preuss

Todd Preuss

Posts: 1

February 14, 2011

Why should we ever think there's just one best model? Generalizations need to be based on comparative studies.
Avatar of: anonymous poster

anonymous poster

Posts: 20

February 14, 2011

I'm not sure if these observations take into account that the gestation period of mice is shorter than that of cows.
Avatar of: Susan Fitzpatrick

Susan Fitzpatrick

Posts: 10

February 14, 2011

Hopefully, there are no hands in the air. We have to stop expecting the mouse to serve as the proxy for "mammal". It isn't. It is also time for scientists to resume educating their trainees about model selection. It is not trivial. Rather it is one of the most important scientific decision researchers must make. At one time this was explicitly known. Today - experimental models are handed down from one generation to the next like some family heirloom. Somewhere along the line the inheritor stops knowing why the item is revered - only that it is.
Avatar of: anonymous poster

anonymous poster

Posts: 13

February 14, 2011

Quoting the article: "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."\nOr maybe it is, pretty much. Maybe cattle are the outliers, maybe all three differ in some ways.\nClearly, comparative studies involving primates are needed to clarify the issue somewhat. What impact does the differing Ts factor have on other aspects of early development. What other factors might differ in parallel? In any case, one would not want to entirely discredit the vast body of data obtained from rodents based on one variance in timing. Yes, use of not-very-human-like model organisms must be considered with caution, but is, of course, an unavoidable economic reality
Avatar of: David Hill

David Hill

Posts: 41

February 14, 2011

Primates are very close to rodents (and lagomorphs, or rabbits), so that in general we should see much more similarity between mice and men. Hooved mammals are much more distant. This does not mean that there are not specific traits in which primates are more similar to hooved animals. As noted in the article, there may be some convergence. This may be related to size or gestation period. But in general, I'd bet on the similarity of the mouse to man.
Avatar of: Hugh Fletcher

Hugh Fletcher

Posts: 44

February 15, 2011

About 90% of bovine twins share a placental circulation, and if they are mixed sex the female is sterilized by testosterone from her brother, becoming a freemartin. This doesn't happen in mice or humans, where it would greatly reduce fitness. Occasional occurrences in other ruminants suggests that at one time an ancestral species only had single embryos, and placental development/identity was relaxed. This may relate to the tolerance of a mutation causing relaxed regulation of a transcription factor in cows' extra-embryonic membranes.\nTwin bovines also swap circulating stem cells.
Avatar of: Leila Elan

Leila Elan

Posts: 1

February 18, 2011

Why do we think that something can model something else?\nMice, cows and primates, they are all complex systems...
Avatar of: Jerry Jones

Jerry Jones

Posts: 12

March 16, 2011

I love Behringer's work and agree fully with his statements but we should emphasize that working with models have advantages not only for human health but for our awareness in general. \n\nMoreover, not all should be working on novel model systems, regardless of whether it's closer or farther from humans. There was a LOT of work developing genetics in these systems and should be utilized to its fullest. \n\nThe statement that cows are closer to humans do not discriminate between cow stomach development being farther from humans than mouse stomachs. We can learn a lot from the recognition that evolution of modularity affects our choices to compare.

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