Mice and Rats Not Best Research Model for Large Mammals

11 February 2011

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.

ENDS

© Scoop Media