The completed draft sequence of the whole human genome was pubished this past February. Now, during this post-genome sequence era, it is very important to study the function of each gene in vivo. For this purpose, transgenic mice and gene targeted knockout mice are two of the most useful tools. Here I have described three examples where such tools were used to analyze the functions of genes responsible for a few obstetric or gynecological diseases. One example of the use of a transgenic mouse model to analyze such a disease is that of the human papillomavirus(HPV) that is associated with cervical cancer. HPV has been shown to be a primary cause in the development of cervical cancer. Specifically, HPV type 16 is detected in over 50% of cervical cancer tissues worldwide, where the HPV genome is integrated into the host genome in these cancer tissues. Both the E6 and E7 genes of HPV have transformation activity and the mechanisms of transformation used by these genes are known in detail. Briefly, the E6 gene product triggers degradation of the tumor suppressor gene p53 through ubiquitination, while the E7 protein detaches another suppressor gene product, Rb, from E2F. To analyze the functions of the E6 and E7 gene products in vivo, transgenic mice were made by several institutes. One report described the use of the keratin 14 promoter to drive expression of the HPV16 E6/E7 genes, which resulted in hyperplasia and dysplasia in the skin of the transgenic mice but no development of cervical cancer was observed. When the genetic background was changed to the FVB/c strain of mice through back-crossing, squamous cell carcinoma developed in the skin, but again, there was no development of cervical cancer. In addition, following administration of estrogen to these mice, squamous cell carcinoma developed in the vulva, the vagina and the cervix. Interestingly, the neoplastic change began at the squamo-columner junction. This mouse model suggested that the HPV E6/E7 genes alone were not sufficient to initiate the development of malignant tumors, rather, the genetic background of the mice was a function of carcinogenesis, and estrogen levels played a role in the development of cervical cancer. The second example of an obstetric study using a transgenic mouse model is of the parvovirus B19 and its association with hydrops fetalis. This virus infects the fetus through the placenta, and induces apoptosis of erythroid lineage cells, resulting in severe anemia of the fetus. The NS1 gene product of this virus is known to be the responsible gene, which stops the cell cycle at the G2/S stage while additionally affecting the caspase cascade. NS1 transgenic mice were established by using the cre/loxP system to maintain mouse lines and the GATA1 promoter to express the transgene in erythroid cells. The majority of the fetuses expressing the NS1 gene were aborted in utero. The fetuses were severely anemic in utero and some of them displayed a hydropic appearance. Blood insulare in the liver of the affected fetuses were seldom found. These results indicated that the NS1 gene of the parvovirus was sufficient for the development of hydrops fetalis and fetal death ; however, it can not be ruled out that other factors might influence the development of these phenotypes. Lastly, as an example of the use of a gene targeted knockout mouse model in the field of obstetrics and gynecology, there is that of the pten gene associated with endometrial cancer. The pten gene has been reported to be mutated in approximately one half of all endometrial cancer cases. The function of this gene and its associated factors were studied in detail. To analyze such an intrinsic gene as pten, gene targeting is a useful technique. Knockout mice with homozygous targeting of the pten gene died in utero at E6.5 to 9.6 days. However, heterozygous pten gene targeted mice exhibited endometrial hyperplasia, with endometrial cancer developing only after 26 weeks of age. These mice all exhibited autoimmune disease and many different types of cancer developed throughout their bodies before endometrial cancer developed. In order to make a more sophisticated model for endometrial cancer, conditional gene targeting appears necessary. In the field of Obstetrics and Gynecology, genetically altered mice such as those described above will become powerful tools to dissect the pathogenesis of a variety of diseases.
|ジャーナル||Acta Obstetrica et Gynaecologica Japonica|
|出版ステータス||Published - 2001|
ASJC Scopus subject areas
- Obstetrics and Gynaecology