January 19, 2005
La Jolla, CA – Scientists at the Salk Institute have discovered a novel genetic pathway that ensures body organs develop correctly and in the right position during embryonic development. The discovery has important implications for stem cell medicine, which continues to face the challenge of inducing stem cells to form new organs.
A team headed by Juan Carlos Izpisúa Belmonte, a professor in the Salk Institute’s Gene Expression Laboratory, has determined that three key genes make the difference between having healthy organs correctly aligned along the midline of the body and deformed organs in the wrong place altogether. The findings were published in the January 1st issue of Genes & Development.
“It’s not enough to tell a cell, ‘you are going to become a cardiac cell,’ said Belmonte. “You also need to tell it, ‘you will be part of the anterior wall of the heart’ – you need to tell each cell its role in the whole organ. We don’t know too much about that. That’s the second level of complexity we need to understand if stem cell therapy is to reach the clinic.”
The incredibly complex process of pattern formation involves cells in the developing embryo getting together, starting to communicate, and migrating into the right places to form an organ such as the heart (cell migration). The process is clearly under genetic control but the genes involved were not known previously. At various points in development genes are turned on and off, acting as blueprints to allow cells to manufacture signaling proteins by which the cells communicate with one another.
“Although scientists in the field understood the actual process of cell migration we didn’t know what players were involved in the migration of these cells in the embryo context. Now we do,” said Salk research associate Takaaki Matsui, leading author of the paper.
The three crucial genes, wnt4a, silberblick/wnt11, and wnt11-related, encode three signaling proteins in a well-known family of proteins called ‘Wnt’. The Wnt proteins have long been implicated in other aspects of development but until the work of the Salk team no-one suspected that they were involved in pattern formation. By a painstaking process of elimination over two-and-a-half years, the Salk scientists demonstrated that blocking these three genes prevented crucial body organs such as the heart, gut, liver and pancreas from lining up along the midline of the body during embryonic development.
The scientists were suprised at what they found. “It’s a complex pathway, much more complex that we are used to,” said Salk senior research associate Angel Raya, co-author of the paper. “Instead of downregulating one gene, because their functions partly overlapped one another we needed to downregulate three genes at the same time in order to get this result.”
For their study, the researchers used the embryo of the zebrafish, an ideal model embryo because it is large, transparent and develops quickly. “You can see everything, right in your petri dish,” said Belmonte.
The discovery of the novel Wnt genetic pathway has important implications for stem cell medicine, which is having some success at changing the fate of stem cells to become replacement nerve or heart tissue cells but is still struggling to persuade cells to form new organs. “Our results give insights into how cells migrate to form tissues and organs,” said Belmonte. “These genes control cell behaviour, rather than cell fate.”
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
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