ASGSB 1998 Annual Meeting Abstracts

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TRANSGENIC MODELS TO STUDY REPRODUCTION, ONCOGENESIS, AND DEVELOPMENT.   M.M. Matzuk, Departments of Pathology, Molecular and Human Genetics, and Cell Biology, Baylor College of Medicine, Houston, TX.

In mammals, there are approximately 100,000 genes which govern the development of an organism. For development to proceed normally, there must be coordinate interaction of thousands of these gene products in any given cell of the being. Beginning with fertilization, precise expression of these gene products is required during embryonic, fetal, post-natal, and adult development. Aberrant synthesis of even one of these gene products can be disastrous - birth defects, cancer, infertility, and even death are all possible when this developmental program is altered. To fully understand these processes in humans, it is necessary to have physiological models that closely mimic developmental events which occur during the creation of a human being.

It is now possible to manipulate the mammalian germline to generate transgenic mice that either overexpress a wild-type or mutant gene or lack a functional copy of an endogenous gene. Studies in my laboratory have been directed at elucidating some of the critical gene products involved in both normal and abnormal mammalian development. Using ES cell technology, we have created several mouse models which have reproductive or developmental defects. Female mice deficient in growth differentiation factor 9 (GDF-9), follicle stimulating hormone (FSH), and activin receptor type II (ActRII) are infertile due to blocks at specific stages of folliculogenesis leading to infertility. Furthermore, mice lacking the ? inhibin gene develop ovarian and testicular tumors in the adolescent stage which resemble juvenile granulosa cell tumors which arise in young girls. Lastly, we have also created a number of models for birth defects. For example, mice with mutations in the activin ?A and follistatin genes have cleft palate, a common birth defect in human infants. These and newly created transgenic mice will continue to be useful in vivo models to study reproduction, oncogenesis, and development.

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