Collagens are the predominant proteins in connective tissues of higher eukaryotes. Several collagens, such as type I, are found in nearly all connective tissues, but display quantitative vacation among cell type. Others, such as type II, display cell type specific distribution. The major goals in this laboratory are the identification of sequences within the collagen genes which are important for establishing qualitative and quantitative variations in collagen synthesis during development, and the identification of cellular factors which interact with those sequences. Particular emphasis will be placed on chondrogenesis, the differentiation of mesenchyme into cartilage, since as the cells differentiate they cease synthesis of type I and initiate synthesis of type II collagen. The specific questions to be addressed are as follows: 1. Are cell type specific differences in collagen synthesis determined by modulation of transcription rates or RNA stability or both? Preliminary data indicate that some differences in RNA levels reflect differences in RNA stability. Sequences and factors which influence RNA stability will be identified. 2. Are variations in collagen synthesis dictated by utilization of different transcription start sites? Preliminary data indicate that transcription of the 2(I) collagen gene initiates at a different site in chondrocytes than in other cell types. Factors which determine cell-type-specific utilization of transcription start sites will be identified, and the effects of start site selection on RNA stability and utilization will be determined. 3. Are variations in collagen synthesis influenced by translational discrimination between RNAs encoding different collagen types? Preliminary data indicate that type II collagen RNA is preferentially translated in chondrocytes, while translation of the 2(I) collagen RNA is prevented by an elongation block. Sequences and factors responsible for that translational discrimination will be identified. The information provided by these experiments will give increased insight into the developmentally regulated expression of the types I and II collagen genes; perhaps most important, it will help determine the molecular basis for the cessation of type I and the initiation of type II collagen synthesis during chondrogenesis.
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