FUNCTIONAL ANALYSIS OF ACTIVINS DURING DEVELOPMENT

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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 tens 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, postnatal, 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. Toward this end, we have chosen the mouse as the mammalian model for our studies. It is now possible to modify the mouse genome to generate strains of mice with precise genetic mutations. Using this technology, our laboratory has created several models which have birth defects. For example, mice with mutations in the activin betaA and follistatin genes die at birth and have cleft palate, a common birth defect in humans of unknown etiology. In addition, mice a mutations in the activin receptor type II gene have skeletal and facial abnormalities which mimic the human Pierre-Robin syndrome; human newborns with this syndrome have defects in the mandible, leading to respiratory distress which must be surgically corrected immediately. In this grant proposal, we will utilize these previously created mouse models as well as additional models (i.e., mice lacking activins betaC an betaE) to study this complex signal transduction system. The Specific Aims are: 1) Define the functions of the liver-specific TGF-beta-superfamily members, activins betaC and betaE; 2) Perform an activin betaB "knockin" to attempt a rescue of activin betaA knockout mice; and 3) Study the postnatal functions of follistatin and activin betaA using inducible knockout systems. Future studies using these mice as in vivo mammalian model systems will enable us to more fully understand the interrelated roles of these proteins in mammalian development and physiology.