Our program includes the following:
1. Cloning of Xenopus MMPs and TIMPs.
2. Characterization of the spatial and temporal expression patterns of MMPs and TIMPs in Xenopus embryos.
3. Biochemical analysis of MMPs, TIMPs and their interactions in Xenopus embryos.
4. Molecular genetic and functional analysis of MMPs and TIMPs in Xenopus early development.
Compared to cell signaling by secreted factors, such as growth factors,
little is known about signaling by the extracellular matrix (ECM), and how
it specifies cell fate and regulates the formation of tissues and organs
during development. The ECM is a ubiquitous complex structure of
collagens, glycoproteins and proteoglycans in all multicellular animals.
In addition to its structural function, recent studies have shown that
degradation and remodeling of the ECM by proteolytic enzymes called matrix
metalloproteinases (MMPs) play important roles in development, tissue
remodeling and disease.
MMPs are a superfamily of zinc endopeptidases; 19 different MMPs have been cloned and characterized including two novel MMPs that we recently cloned from chicken and the frog Xenopus laevis.
Many MMPs are expressed widely during embryogenesis, but not in adult life, often in a highly cell and tissue-specific pattern suggesting distinct roles for different MMPs in growth and development. In adult life, MMPs are expressed in rapidly remodeling tissues such as menstrual endometrium, term placenta, involuting mammary glands, and during wound healing and inflammation. MMPs are also thought to play a critical role in tumor growth and metastasis, and in the progression of other diseases such as arthritis, atherosclerosis and aneurysm. MMPs are inhibited by their specific naturally occuring inhibitors called tissue inhibitors of metalloproteinases (TIMPs). Four different TIMPs have been cloned and characterized.
Our long term goal is to understand the roles of MMPs and TIMPs in development, tissue remodeling and disease. Recently, we initiated a research program to study MMPs and TIMPs in vertebrate early development, using the frog Xenopus laevis as a model organism. At present, we have cloned TIMP3 and six different MMPs from Xenopus> including a novel member of the MMP family called XMMP. As shown by Northern blotting and RT-PCR, the XMMP gene is first transiently expressed in gastrula and neurula stage embryos, and then downregulated in pretailbud embryos. In contrast, TIMP3 mRNA is maternally inherited in eggs and blastula, downregulated in gastrula and then upregulated in neurula and pretailbud embryos.
November 26, 1997