Major research fields
Developmental Biology, Organ Formation
In many forms of organogenesis, we can observe the coordinated movement of epithelial cells in tubes. For example, in the development of the lung, tubular epithelial sheets repeatedly extend and subdivide in branching patterns and thereby giving rise to the minutely ramified and intricate structure of the airway. Epithelium is characterized by the presence of a basement membrane, an extracellular substrate in the form of a protein matrix, which plays important roles in regulating the direction and distance of epithelial cell migration.
We study the function of basement membranes in migration of epithelial tubes using a model organism called C. elegans, which is a species of tiny roundworm about 1 mm in length. In this worm, the gonads develop following a stereotyped pattern in which cells at the leading end of the migrating gonad (known as distal tip cells, or DTCs) travel along a U-shaped route in the larval body, thereby giving rise to an organ of that shape. The proper migration of the developing gonad relies on surface interactions mediated by the basement membranes of the gonad and the body wall. We study various mutant worms in which the direction of gonadal cell migration is abnormal to search for clues to the genetic and molecular bases of DTC guidance. One of the genes we have been focusing on encodes a metalloprotease named MIG- 17, which localizes in the gonadal cell basement membrane and plays an important part in the determination of the DTC's migratory route by breaking down or modifying other membrane proteins. We have also discovered that a member of the fibulin family of secreted proteins is localized to the basement membrane in response to MIG-17 activity and also plays a role in directing cell migration. It is our hope that this sort of research will provide insights into basic biological mechanisms that make it possible to treat a range of health conditions in which cell migration is aberrant.
Major relevant publications
- Kim, H-S., Kitano, Y., Mori, M., Takano, T., Harbaugh, T. E., Mizutani, K., Yanagimoto, H., Miwa, S., Ihara, S., Kubota, Y., Shibata, Y., Ikenishi,K., Garriga, G., and Nishiwaki, K. (2014). The novel secreted factor MIG-18 acts with MIG-17/ADAMTS to control cell migration in Caenorhabditis elegans. Genetics 196: 471-479.
- Shibata, Y., Sawa, H., and Nishiwaki, K. (2014). HTZ-1/H2A.z and MYS-1/MYST HAT act redundantly to maintain cell fates in somatic gonadal cells through repression of ceh-22 in Caenorhabditis elegans. Development 141: 209-218.
- Kim, H.-S., Murakami, R., Quintin, S., Mori, M., Ohkura, K., Tamai, K., Labouesse, M., Sakamoto, H., and Nishiwaki, K. (2011). VAB-10 spectraplakin acts in cell and nuclear migration in Caenorhabditis elegans. Development 138: 4013-4023.
- Kubota, Y., Ohkura, K., Tamai, K. K., Nagata, K. and Nishiwaki, K. (2008). MIG-17/ADAMTS controls cell migration by recruiting nidogen to the basement membrane in C. elegans. Proc. Natl. Acad. Sci. USA 105: 20804-20809.
- Ihara, S. and Nishiwaki, K. (2007). Prodomain-dependent tissue targeting of an ADAMTS protease controls cell migration in Caenorhabditis elegans. EMBO J. 26: 2607-2620.