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Double trouble

Why cloned animal embryos are frequently aborted

Munich, 04/14/2009

Cloning – the production of animals by somatic cell nuclear transfer – facilitates targeted genetic modification of livestock and allows breeders to preserve successful genetic constellations. But even in cattle, the animal in which the best results have been achieved to date, cloning remains very inefficient. Just ten out of every 100 embryos transferred to recipient animals – surrogate mothers – will grow into living calves. “Structural or functional changes in the placenta frequently occur in cloned cattle embryos, leading to termination of the pregnancy,” reports Professor Eckhard Wolf, LMU Munich Gene Center. A team headed by the professor of veterinary medicine has now looked at whether this is the result of impaired molecular communication between the embryo and the endometrium (the lining of the uterus). The team measured gene activity in endometrial cells following transfer of embryos produced either by cloning or through in vitro fertilization. It turned out that there are indeed differences in gene activity – determined by measuring the concentration of different messenger RNAs – between the two groups. The frequent occurrence of placental changes in clone pregnancies is therefore probably due to disturbances in molecular communication prior to the implantation of the embryo. Determination of gene activity could thus provide an early indication of possible problems and offer new approaches to improving cloning techniques.

“Animal breeding is based on the selection and reproduction of outstanding animals,” notes Professor Wolf. “This principle has not changed since the domestication of animals more than 10,000 years ago. Today, cloning – the production of genetically identical animals – is a kind of insurance policy. If a breeder has a particularly valuable bull, cloning allows him to ensure that he preserves the animal's specific genetic constellation. Cloning is also currently the only procedure available for performing targeted genetic modification of livestock. Examples include the production of therapeutic proteins in the mammary glands of cows and the cloning of pigs for xenotransplantation – the transplantation of animal tissue or organs into humans to replace diseased tissue.”

For applications such as this, cloned embryos with targeted modifications to their genetic material are implanted into the uterus of a surrogate mother, which then carries the embryo to term. The success rate for this type of transfer, however, remains disappointingly small at present. "We tested the hypothesis that early embryo-maternal communication is impaired," says Wolf. “We have been researching this issue for several years in a research group supported by the Deutsche Forschungsgemeinschaft. In this study we tested whether the endometrium reacts differently to cloned embryos than to embryos produced through fertilization.” The experiment involved transferring both groups of embryos to recipient mothers and taking samples from the lining of the uterus ten days after transfer.

A DNA microassay specifically designed for this experiment by Dr. Stefan Bauersachs’ team at the Laboratory for Functional Genome Analysis (LAFUGA) at LMU’s Gene Center was used to analyze the pattern of gene activity in the extracted cells. The study found clear differences. Of the roughly 1000 genes on the chip, more than 50 showed altered activity in many of the samples from clone pregnancies. From mouse studies, it was already known that some of these genes play a crucial role in implantation of the embryo in the endometrium. To exclude the possibility that this effect was due to a specific random genetic combination, cell lines from a total of seven different donor animals were used for cloning and tested - with consistent results.

“These results allow us to draw an important conclusion,” says Wolf. “We can now say that there is a very high probability that the frequent occurrence of placenta changes in clone pregnancies in cattle is due to impaired embryo-maternal communication. As our results show, it is possible to detect this impairment with a high level of sensitivity by determining molecular patterns – in this case patterns of gene activity. We have thus developed an early and very sensitive indicator which can be used for enhancing cloning techniques." (suwe)

“The endometrium responds differently to cloned versus fertilized embryos”,
Stefan Bauersachs, Susanne E. Ulbrich, Valeri Zakhartchenko, Megan Minten, Myriam Reichenbach, Horst-Dieter Reichenbach, Helmut Blum, Thomas E. Spencer, and Eckhard Wolf
PNAS 106: 5681-6, 7 April 2009

Professor Eckhard Wolf
Gene Center of the LMU Munich
Tel.: 089 / 2180 – 76800
Fax: 089 / 2180 – 76849

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