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Seeking The Molecular Basis Of Limb Regeneration

Why can some animals so easily regenerate severed body parts? What molecularmechanism makes this feat possible at all? The answers to this crucial questionhave eluded researchers for over 250 years. Now there are some promisinganswers.

Carnegie Institution of Washington, Department of Embryology scientistsAlejandro Sánchez Alvarado and Phillip A. Newmark have demonstratedthat the introduction of specific double-stranded RNA molecules into cellsassociated with tissue regeneration in flatworms alters those cells' behavior.

This is a major step in trying to understand the molecular mechanismsdictating why some animals are able to regenerate missing body parts. Thestudy was reported in the April 27 Proceedings of the National Academyof Sciences.

Flatworms are attractive as research subjects because their regenerativeabilities are quite pronounced: Their rate of regeneration is faster thanthat of most amphibians, the traditional vertebrates used to study thisproblem.

The scientists chose three well-characterized tissue types to study inthe S. mediterranea flatworm: the body-wall musculature, the ciliated ventralepithelium and the worm's photoreceptors.

In the case of the first tissue, flatworm fragments were cut and injectedwith a specific double-stranded RNA (dsRNA) targeted to interfere with thesynthesis of the protein responsible for muscle contraction. The objectivewas to see if cell differentiation, particularly muscle differentiationin the blastema -- the regeneration bud from which the missing body partswill emerge -- was affected.

The fragments were allowed to heal and regenerate for at least threedays. After careful analysis, the animals injected with the double-strandedRNA showed "very little, if any, regeneration of the body-wall musculaturewithin their blastemas." The scientists also found that pre-existingmusculature was affected. Cells in the controls, however, had started toregenerate normally.

The specificity of the double-stranded RNA was determined in two ways.First, the dsRNA that disrupted body-wall musculature formation was injectedinto the worms and the regeneration of tissues that should not be affected,such as the ciliated ventral surface, was shown to be normal. Conversely,a dsRNA that interfered with the regeneration of the ciliated ventral surfacewas applied to the flatworms and shown to affect only its target tissue,while allowing the regeneration of the body-wall musculature to proceednormally.

Although the mechanism by which the dsRNA inhibits gene expression isnot entirely clear yet, the researchers showed that as in C. elegans, anematode, it acts by eliminating the endogenous levels of the targeted messengerRNA transcripts.

According to Principal Investigator Sánchez Alvarado, "Thedemonstration that genes can be silenced during the process of regenerationopens the door to the molecular dissection of this long-standing problemof biology. Eliminating the expression of those genes, which are modulatedby regeneration, will help researchers identify those factors which allowregeneration to occur in some, but not all multicellular organisms."

This research was supported by the National Institutes of Health, NationalInstitute of General Medical Science and the Cancer Research Fund of theDamon Runyon-Walter Winchell Foundation.


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