The function of tubular organs like the kidneys, lungs, and vessels of
the vascular system is critically dependent on the length and diameter
of the tubular branches of which they are composed. Several devastating
pathological conditions like polycystic kidney disease and ischemias
have been intimately linked to the aberrant sizes of tubular organs.
Yet the underlying cellular and molecular mechanisms that control tube
size are poorly understood, and, consequently, drugs that intervene in
tubular organ disorders are lacking.
Over the past few years, the tracheal system of the fruit fly
Drosophila has provided important general insights into epithelial
organ morphogenesis. The fly’s tracheal system is a tubular network
that functions in respiration by transporting oxygen throughout the
insect body. In two separate new studies, researchers have taken
advantage of the usefulness of the Drosophila tracheal system as a
model for understanding the development of tubular organs. Both studies
point to the important role played in this process by the luminal
extracellular matrix (ECM)–a scaffold of sorts that provides structure
to surrounding cells and tissues. Past work had shown that inside the
tracheal tube, or lumen, the polysaccharide molecule chitin forms a
cylinder that is essential for the coordinated dilation of the
surrounding epithelium to its normal mature size: Mutants lacking
chitin show tubes with irregular diameter.
In one of the new studies, a group led by Christos Samakovlis
at Stockholm University has revealed further evidence for an
"instructive" function of the luminal ECM in tube size control. They
found that while uniform expansion of tube diameter requires the growth
of a luminal chitin scaffold, the subsequent modification of this
chitinous mandrel by specialized enzymes (called chitin deacetylases)
instructs the termination of tube elongation. Mutations in two genes
encoding these enzymes disrupt tubular morphogenesis. The authors’
additional discovery that proper luminal localization of one of the
chitin deacetylases requires a specialized secretory pathway and intact
structures called paracellular septate junctions provides a mechanistic
model for tracheal tube size regulation.
The other new study, from Stefan Luschnig and colleagues at
Bayreuth University, Germany, and at Stanford University, reports a
similar set of findings. These researchers also identified the two
chitin deacetyase genes as specifically controlling tube length. As did
the Samakovlis group, the researchers found that mutations in these
genes, called serpentine (serp) and vermiform (verm), cause excessively
elongated and tortuous tracheal tubes. Unlike previously characterized
genes, serp and verm are not required for producing chitin, but rather
are required for its normal fibrillar structure. The findings of the
two groups suggest that tube length is controlled by modulating
physical properties of the chitin cylinder. These properties may be
sensed by tracheal cells, mediating the restriction of cell elongation.
Given the many similarities in the developmental mechanisms and
cellular designs of tubular organs across species, the distinct roles
of the luminal ECM in tracheal tube size control provide new leads in
the investigation of lumen size regulation in a variety of tubular
organs.
Source: Cell Press. January 2006.