Researchers feed tiny pills of RNA to planarians to identify genes essential for

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Researchers feed tiny pills of RNA to planarians to identify genes

essential for regeneration

03 May 2005 Medical News Today

University of Utah researchers-feeding microscopic pills of RNA to

quarter-inch long worms called planarians-have identified many genes

essential to understanding a biological mystery that has captivated

scientists for hundreds of years: regeneration.

In pinpointing the genes, the U School of Medicine researchers have

established the planarian as a genetically sound model for human

biology, to take its place alongside Drosophila (fruit flies),

C.elegans (another worm), zebrafish, and mice.

The study, to be published in the May issue of Developmental Cell,

employed the first large-scale use of RNA interference (RNAi) to

silence planarian genes to identify their role in the worm's biology,

according to Sánchez Alvarado, Ph.D., principal

investigator and U medical school associate professor of neurobiology

and anatomy. The U team's work shows that planarian genes can be

selectively manipulated to study some of the most basic and important

areas of biological research: stem cells, homeostasis (tissue loss

and replacement), regeneration, and disease.

" Planarian biology has much in common to the biology that you and I

share, " said Sánchez Alvarado, who last month was appointed a

Medical Institute investigator. " This work opens a whole new

window to study aspects of human biology that are barely accessible

today. "

The planarians used in these studies, also called flatworms, live in

fresh water and have a singular ability to regenerate. Chop one in

half, and two new worms grow. Their ability to regenerate is so

prolific that a tissue fragment only 1/279th of the worm's length can

grow into a new planarian. Researchers know that planarian stem

cells, called neoblasts, play a central role in both regeneration and

homeostasis. But how they do that has remained shrouded in mystery.

Sánchez Alvarado and his research associates used bacteria to

synthesize double-stranded RNA that silences planarian genes. The

bacteria effectively become tiny pills-five to 10 microns across-that

now can be mixed into planarian food. When Sánchez Alvarado and his

associates fed the worms dinner, the RNA diffused throughout their

bodies.

Sánchez Alvarado and Helen Hay Whitney Foundation postdoctoral fellow

W. Reddien, Ph.D., silenced and screened 1,065 planarian genes

with RNAi. Specific defects were associated with 240 of the genes

that were silenced. About 85 percent (204) of the 240 genes are

shared by the genomes of other species, including humans, according

to Sánchez Alvarado.

The researchers found that 145 of the silenced genes affect both

regeneration and tissue loss and replacement. Some of the genes were

essential to homeostasis, but not regeneration, and 35 genes were

found to be essential to regeneration, but not homeostasis.

" This tells us that separate genetic pathways for regeneration and

homeostasis must exist, " Sánchez Alvarado said. " It's a huge step

forward for us and opens the possibility of systematic molecular

studies to find the genetic cause of regenerative processes in

animals. "

Silencing planarian genes may also help in studying human disease.

Thirty-eight of the genes Sánchez Alvarado and his team silenced are

related to human genes associated with diseases, such as ataxia

(inability to coordinate muscular movements), bradyopsia (slow

vision), and cancer. Only eight of those genes have a corresponding

knockout gene in mice. This means researchers may be able to use

planarians to learn about human diseases that can't be studied in

other animal models.

Another 35 of the silenced genes may shed light on the parasitic

platyhelminthes, such as Schitosoma mansoni, which cause disease in

millions of people. The genes identified by the U researchers may be

required for the survival of the parasites.

" Considering such pathogens are estimated to cause disease in nearly

300 million people throughout the world, these genes might make

attractive drug targets, " Sánchez Alvarado and his fellow researchers

wrote in the study.

The planarian makes an ideal biological model for three important

reasons, according to Sánchez Alvarado.

-- It is amenable to genetic manipulation.

-- It is an extremely simple organism with little redundancy in its

genes, meaning it has fewer genes to carry out specific functions.

This makes it easier to identify a gene's function by silencing it

and will help how researchers target their efforts on equivalent

genes in mice or zebrafish, for example.

-- It is inexpensive to study.

Now that Sánchez Alvarado and his colleagues have opened the door to

understanding regeneration by identifying key genes in the process,

the U researcher predicts, with aid of the planarian, more

discoveries are on the way.

" Our limitations right now are how many experiments we can do in a

day, " he said. " The mystery of what makes regeneration possible,

particularly in these animals, is on its way to finally being

resolved. "

Other authors of the study include W. Reddien, Ph.D, Helen Hay

Whitney Foundation postdoctoral fellow, J. Murfitt, and Joya

R. Jennings, all of the University of Utah Department of Neurobiology

and Anatomy in the School of Medicine; and Adam L. Bermange,

currently at the London Research Institute.

This news release and a downloadable, high-resolution photograph will

be available at this Web site at noon (EST) on Monday, May 2.

http://www.utah.edu/unews/releases/05/may/planaria.html