麻豆淫院

The lab of Dr. Mark Magnuson, Louise B. McGavock Professor and professor of molecular physiology and biophysics at Vanderbilt University, has demonstrated that the formation of the gallbladder and bile duct system depends on the concentration of a transcription factor鈥擲ox17鈥攁nd that a small reduction in the amount of Sox17 results in mice that lack a gallbladder.

The paper, in Development and completed in collaboration with Professor of Cell and Developmental Biology Christopher Wright, describes how the formation of the gallbladder and extrahepatic bile ducts (which route bile produced by the liver into the small intestine) is exquisitely sensitive to the concentration of Sox17.

Transcription factors increase or decrease the expression of target genes, and those genes are sensitive to changes in transcription factor concentrations鈥攕ome more than others. To that point, there is mounting evidence that altered or dysregulated levels of Sox transcription factors, such as Sox2, Sox9, and Sox17, impair the development of multiple tissues both in mice and in humans.

"Sox17 is essential for the formation of the liver, pancreas, and gallbladder, as well as the ductal and vascular network that link these vital organs," Magnuson said. "We refer to it as the hepato-pancreato-biliary (HPB) system." Magnuson is also the director of the Center for Stem Cell Biology.

The Sox17 gene has two sites where Sox17 mRNA transcription begins, and it is not understood how either start site is regulated. To determine whether mRNA transcripts originating from the second site in Sox17 regulate HPB formation, the Magnuson lab used CRISPR/Cas9 mutagenesis in mice to mutate two predicted transcription factor binding sites within this region. However, they also unexpectedly obtained a 50鈥揵ase pair deletion within this key regulatory region.

"When we performed a necropsy on the mice with the deletions, we found that they had no gallbladder," Magnuson said. The observation spurred further investigation and resulted in the Development paper.

The paper, which was led by graduate students Linh Trinh and Ryan Finnel, strongly indicates that formation of the gallbladder and bile duct system requires precise control of Sox17 expression. This likely means that gradients that control Sox17 expression or action modulate the formation of the gallbladder and the ductal system, and sufficiently large reductions in Sox17 prevent their formation altogether.

One key discovery that the Magnuson lab made was that the Sox17 gene itself contains a binding site for the Sox17 protein, which creates a positive, autoregulatory feedback loop that increases Sox17 expression above the threshold necessary for biliary progenitor cells to form the gallbladder and bile duct system.

"We also found that mice with a reduced expression of Sox17 exhibit metaplastic transformation," Magnuson said. In this context, metaplasia refers to cells that undergo a change to resemble another cell type; for example, stomach cells that transform to look like intestinal cells are metaplastic.

"The metaplastic transformation we observed is similar to that seen in several human conditions, such as gallbladder cancer," added Magnuson.

Trinh and Finnel's work provides important new insights into the formation of the gallbladder and extrahepatic biliary ducts, and may in time help researchers understand, prevent, or treat diseases of the gallbladder, such as biliary atresia鈥攁 childhood disease in which one or more bile ducts in the liver are abnormally narrow, blocked, or absent鈥攁nd cholangiocarcinoma鈥攃ancer of the bile ducts.

In the meantime, the Magnuson lab will continue to explore how Sox17 regulates genes that are critical for formation and function of the gallbladder and bile duct system.