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Kiyoji NISHIWAKI, Ph. D. 
In
many forms of organogenesis, we can observe the coordinated movement of
epithelial cells in sheets. For example, in the development of the lung,
tubular epithelial sheets repeatedly extend and subdivide in branching
patterns and thereby give 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. The main component of the basement membrane
is collagen, but it comprises hundreds of other proteins as well, and
abnormalities in the function of these proteins can lead to a range of
developmental anomalies and pathologies.
We
study the function of basement membranes in migration of epithelial sheets
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 research
such as this will provide insights into basic biological mechanisms that
may one day make it possible to treat a range of health conditions in
which cell migration is aberrant.
