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 linkurl:research;http://www.cell.com/developmental-cell/abstract/S1534-5807(11)00004-9 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,;http://bcrt.charite.de/index.php?id=47 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,;http://med.stanford.edu/profiles/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,;http://www.agresearch.co.nz/about-us/our-people/science-staff/pages/profile.aspx?Name-id=pfeffer-peter 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,;http://faculty.mdanderson.org/Richard_Behringer/Default.asp?SNID=1060595112 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;http://www.cell.com/developmental-cell/abstract/S1534-5807(11)00004-9
**__Related stories:__***linkurl:One step to human pluripotency;http://www.the-scientist.com/blog/display/55949/
[28th August 2009]*linkurl:Single-factor stem cells;http://www.the-scientist.com/blog/display/55399/
[5th February 2009]*linkurl:Model Organisms;http://www.the-scientist.com/supplement/2003-6-2/
[2nd June 2003]* linkurl:Related F1000 evaluations;http://f1000.com/search/evaluations?query=Oct4
[14th February 2011]