Before a pancreas is a pancreas, it’s part of the endoderm, one of three layers of cells in a developing embryo that eventually form its organs. Researchers at Rockefeller University have now uncovered key genetic signals involved in how the pancreas begins forming, a finding they say might lead to regenerative therapies for patients with certain forms of diabetes whose pancreases no longer function.
In both frogs and zebrafish, vertebrates that are studied as model organisms because they develop externally and can be easily viewed and manipulated, researchers had some understanding of the genetic signals that cause the endodermic tissue to begin developing into pancreatic tissue. They knew that the gene Gata5 is expressed at the earliest stage of endoderm development, and that at the initiation of organogenesis, in which the organ is already starting to form, the pancreatic marker gene Pdx1 is turned on. But they were missing a key step in the middle.
To find out what happens between Gata5 and Pdx1, Ali Brivanlou, head of the Laboratory of Molecular Vertebrate Embryology, and Francesca Spagnoli, a postdoc in his lab, used a gene microarray in frog embryos to identify 141 genes whose expression depends on Gata5 signaling. Spagnoli then independently verified these genes in other model systems, eventually eliminating all but one: TGIF2. “We found that TGIF2 was a key target of Gata5,” she says. “It is expressed early in the region known to give rise to the pancreas.”
No one knows the function of TGIF2 in adult cells, although overexpression has been found in some ovarian cancers, Spagnoli says. The gene, however, is a member of the TGIF family of genes, one of which, TGIF1, is expressed in the brain and has been linked to a structural abnormality of the brain. “This is interesting to us because there are a lot of similarities between gene expression in the nervous system and that in the pancreas, which doesn’t occur in other organ systems,” she says.
To find out what role TGIF2 plays in pancreatic organogenesis, Spagnoli eliminated its expression in frog embryos and found that a larger liver developed, but no pancreas. The researchers then discovered that TGIF2 controls the expression of the BMP gene, which is part of a family of proteins that play regulatory roles in growth and development. In this case, TGIF2 acts primarily by restricting BMP signaling in the endoderm to allow the formation of the pancreas.
“This finding connects Gata5 to Pdx1, covering the gap of knowledge in the window of time between endoderm induction, patterning and organogenesis,” Spagnoli says. “We find that TGIF2 behaves as a modifier, inhibiting BMP signaling so that Pdx1 can be expressed.” The results are reported in the February 1 issue of the journal Development.
What this means, Spagnoli says, is that researchers might be able to coax a pancreas to form from embryonic tissue by blocking BMP expression. “Already, I have found that if I add some commercial agent that blocks BMP signaling to cell culture, I can induce development of pancreatic cells,” Spagnoli says. “The bottom line is that we hope our findings can be applied to cell-based therapy to create new pancreatic cells for patients who desperately need them.”
The study was funded by grants from the Juvenile Diabetes Research Foundation, the Emerald Foundation and the National Institutes of Health.
Journal reference: The Gata5 target, TGIF2, defines the pancreatic region by modulating BMP signals within the endoderm. Development 135(3): 451–461 (February 1, 2008)
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