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1st appeared
09 December
1999 Zebrafish’s Powerful Heart Gene Could Lead to Transplant Therapy
Researchers have discovered a gene in zebrafish so powerful it can be used to redirect the fate of cells in the developing embryo to become beating heart cells. The research suggests that a similar gene in humans could be used to generate heart cells in culture for transplant in ailing people. The finding, the first discovery of a so-called "master" gene for myocardial, or heart muscle, cells in an animal model, puts researchers on track for exploring the capability of homologous genes in mice and humans.
The gene, known as gata5, acts in embryonic cells, which are primordial, unspecialized cells that form in the earliest stage of embryonic development and are genetically programmed to evolve into one of many specialized cell types, such as skeletal muscle cells, nerve cells, blood cells, skin cells, and liver cells. Normally, the gene acts only in those embryonic cells destined to become myocardial cells. The research shows, however, that gata5 can reprogram otherwise predestined embryonic cell types to become beating heart cells. If zebrafish gata5, or its human equivalent, could prompt a particular type of embryonic cell, known as a human embryonic stem cell, to become a beating heart cell, researchers could theoretically use this technique to cultivate and harvest such genetically modified cells in the petri dish and then transplant them into people with failing hearts. "Discovery of a gene that could convert human embryonic stem cells into myocardial cells would be golden," said Didier Stainier, PhD, UCSF assistant professor of biochemistry and biophysics, the senior author of the UCSF study and a pioneer in the study of heart development in the transparent zebrafish embryo. "Gata5 is potentially such a gene. It appears to be sufficient to drive the entire myocardial program in certain cells not normally fated to contribute to the heart." Stainier and colleagues’ discovery of gata5’s power presented powerful images: Removal of gata5 from cells normally destined to become myocardial cells caused profound defects in the formation of the heart. Expression of gata5 throughout the embryo caused heart cells to form and beat -- spontaneously and rhythmically -- as far away from the head region, where the heart forms, as the animals’ lower trunk. The finding, published in the current issue of Genes and Development, represents a different approach to cultivating specialized cells for transplant therapy than that being pursued in other labs. Current efforts, mostly conducted in animal models, involve attempting to derive and aggregate embryonic stem cells, exposing them to such factors as acetic acid, allowing them to differentiate, or specialize, and then sorting through these cells to extract the cell types of interest. "Using different regulators, scientists have been able to induce a subset of myocardial characteristics in various experimental models, but never the complete beating phenotype, so there is something special about gata5 that can take a cell that’s not supposed to become a heart cell to actually become one," said Stainier. "We’re very excited about this finding." The significance of the UCSF discoveries dramatizes the importance of the tiny blue-and-silver striped denizen of India’s Ganges River -- and many an aquarium -- as a model for biomedical studies. Until recently studied in only a handful of labs worldwide, it is increasingly surfacing at the lab bench. The reasons for its appeal are many, but none rival the fact that the crystal-clear zebrafish embryo offers a view of burgeoning life that no other vertebrate model can. Less than a day after fertilization, the fertilized egg has sprouted a two-chambered beating heart, ears and eyes and a tail that flicks. By the third day, all of its major organs have fully developed and moved into proper position, offering scientists a view of what has been referred to as the zebrafish’s "artful etchings." Less dramatic but of great import, zebrafish, like mice and humans, are vertebrate -- having a backbone and a tubular nervous system divided into the brain and spinal cord -- and are therefore more likely to be genetically similar to humans than non-vertebrate models such as yeast, roundworms and fruit flies (even though the latter have provided valuable information about mechanisms in vertebrate). Moreover, unlike other vertebrate model systems (principally the frog, chick and mouse), the animal offers the opportunity to search for mutations that disrupt specific biological events by a process that does not require prior knowledge of the gene or genes involved. This approach is also used in invertebrate organisms such as Drosophila (fruit flies) and Caenorhabditis elegans (a roundworm). Links: Zebrafish images and descriptions NIH Zebrafish Initiative Web site Genes and Visual Perception -- Through the Eyes of the Zebrafish Source: Jennifer O’Brien, News Services |
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