May 13, 2004
UCSD Biologists
Uncover Genetic Links To Broad Range
Of Human Disorders Resulting From Cilia Dysfunctions
By Kim McDonald
Biologists at the University of California, San Diego have discovered a
number of key genes that humans, mice, fruit flies and roundworms all need
to produce hair-like cellular protrusions known as cilia -- a structure
that when absent or defective in certain cells has been linked to human
infertility, blindness, kidney disease and lung dysfunction.
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Green neurons at base of red sensory bristles on the
thorax of fruit fly. Click here
for high-res image |
In a
paper featured on the cover of the May 14 issue of the journal Cell,
UCSD biologists headed by Charles S. Zuker, a professor of biology and of
neurosciences, and postdoctoral fellow Tomer Avidor-Reiss report the
identification of some 40 genes that play a role in cilia formation, six of
which, they discovered, are essential for the assembly of this cell
structure.
"These six genes
are fundamentally and universally important for any cell to build
cilia," says Zuker, who is also a Howard Hughes Medical Institute
investigator, "because if a cell doesn'thave all of them, it is unable
to grow cilia."
The
discovery of these genes provides medical researchers with a critical new
tool to help in diagnosing genetic diseases involving cilia dysfunction and
possibly in developing drugs thatcan minimize the health effects of such
dysfunctions. .
"This
will provide the basic foundation for researchers to understand how cilia
form and thegenetic basis for so many of these human genetic
disorders," says Avidor-Reiss. "It is only recently that
scientists began to realize that there are links between cilia dysfunction
and a wide range of human genetic diseases. Now we have an exciting
collection of candidate genes."
In humans, sperm
navigate toward the egg by propelling themselves with a type of cilia known
as flagella. Defects in these whip-like cilia, result in non-motile sperm
and male infertility, and are probably the most commonly known type of
cilia dysfunctions. Other widely known human cilia disorders include the pulmonary
diseases caused by defective respiratory cilia, which cleanse the lungs by
sweeping mucous and trapped particles into the throat, and the vision
problems or blindness due to defective cilia in the eye's photoreceptors.
In recent years, that
list has grown as medical researchers discovered that many human genetic
ailments affecting multiple organs have their origin in the absence and
dysfunction of cilia. These include polycystic kidney disease, the most
common genetic cause of kidney failure; embryonic problems in the body's
right-left symmetry that cause organs to develop on the wrong side of the
body; and Bardet-Biedel syndrome, a rare genetic disorder characterized by
obesity, learning disabilities and eye and kidney problems.
"What was
disconcerting about human cilia defects was that, because the physiology of
these diseases are so complex and broad, the disorders were not initially
tied to cilia dysfunctions," says Zuker. "These people have
problems with their retinas, lungs and kidneys. It's only been in the last
few years that scientists have understood the etiological basis of some of
these human genetic disorders."
Unlike other studies
that sought to identify one or two human genes tied to a specific human
cilia dysfunction, Zuker's team started with the entire genomes of a wide
range of organisms ranging from the unicellular parasite responsible for
malaria to humans. The UCSD biologists analyzed more than 150,000 genes
using an ingenious computer-analysis strategy, devised by Avidor-Reiss, to
search for genes uniquely involved in cilia formation and function. That
enabled them to identify approximately 200 genes used by radically
different forms of life to build the basic cilia machinery.
Avidor-Reiss narrowed
the field of 200 again to 40 genes important for a type of cilia found in
human, mouse, fruit fly and roundworm cells, then demonstrated, in a series
of experiments in fruit flies, that six of those genes were integral for
the formation of cilia. This was done by attaching a fluorescent protein to
the proteins produced by the candidate genes that end up at the base of the
fly's back bristles, a form of sensory cilia used by flies to sense their
position in space and steer as they fly (see photograph).
"Using Drosophila,
we were able to demonstrate that all of the genes we have examined were
expressed in ciliated cells by tagging them with green fluorescent
protein," says Avidor-Reiss. "You could just look at the flies
and see them glow."
"What he has now
is a list of very attractive candidates," says Zuker. "What we
have to do now is to assign functions to them, so we can see how they come
together to orchestrate and choreograph the cilia-building and functioning
processes. That's going to be a technically demanding, but exciting
challenge."
Other researchers who
contributed to the study included Edmund Koundakjian and Andrey
Polyanovsky, biologists in Zuker's laboratory; Andreia Maer and Shankar
Subramaniam of UCSD's San Diego Supercomputer Center; and Thomas Keil of
the Max Planck Institute of Biochemistry in Germany. The study was funded
by grants from the National Eye Institute and the Howard Hughes Medical
Institute.
Media Contacts: Kim McDonald (858) 534-7572
Comment: Charles Zuker (858) 534-5528
Tomer Avidor-Reiss
(858) 534-5423