Type XI collagen, a heterotrimer specific to cartilage matrix, plays an important role in cartilage morphogenesis. We analyzed various alpha2(XI) collagen promoter-lacZ reporter gene constructs in transgenic mice to understand tissue-specific transcriptional regulation. The -530 promoter sequence was sufficient to direct reporter gene expression specifically to cartilage. Further deletion to -500 abolished reporter gene expression in cartilage but activated the expression specific to neural tissues such as brain and neural tube. An additional 47-base pair deletion resulted in random tissue expression patterns. A 24-base pair sequence from -530 to -507 of the alpha2(XI) promoter was able to switch the activity of the heterologous neurofilament light gene promoter from neural tissues to cartilage. These results suggest that the alpha2(XI) collagen gene is regulated by at least three modular elements: a basal promoter sequence distal to -453, a neural tissue-specific element (-454 to -500), and a cartilage-specific element (-501 to -530), which inhibits expression in neural tissues and induces expression in cartilage.