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Urinary tract abnormalities occur in almost 1 percent of all infants, which is a very high rate for a genetic defect. Often, an affected newborn will have multiple kidney abnormalities that will be accompanied by defective ureter-bladder connections. But the reason for atypical linkages between the ureter and the bladder has remained unclear.

Columbia University Health Sciences investigators now have the first visual and genetic evidence of how the ureter connects to the bladder during mouse development, providing clues as to how birth defects in this region occur in humans. The findings also may explain how syndromes in which several abnormalities in a single individual arise, because the genes important for the ureter-bladder connection are also essential for forming other parts of the urinary tract, such as the kidney.

The results of the study, led by Dr. Cathy Mendelsohn, assistant professor of urological sciences in urology, pathology, and the Institute of Human Nutrition, were published Aug. 26 in the online version of the journal Nature Genetics. A better understanding of urinary tract genetics and development could lead someday to better prevention and detection of these abnormalities.

The urinary tract helps the body maintain water balance and excrete waste. The body takes nutrients from food and uses them for energy and repair, leaving behind toxic waste products that must be eliminated. The kidneys remove urea, a waste product of protein metabolism, from the blood. Urea, water, and other substances form urine, which travels down two thin tubes called ureters to the bladder. The bladder stores urine until the body is ready to empty it. For the urinary tract to function, proper connections between the kidney, ureter, and bladder must form.

In the research, Dr. Mendelsohn and her colleagues studied the process of normal embryonic development of the urinary tract in the mouse, observing how connections are made between the ureter and the bladder and analyzing the genetics behind the process.

"Before our studies, the mechanism of ureter migration was not understood," Dr. Mendelsohn says.

The investigators were able to observe the complex events that take place as ureters join the bladder using a genetically engineered mouse that expresses a green fluorescent protein in the fetal excretory system. Dr. Franklin Costantini, professor of genetics and development and acting chairman of the department, developed the mouse line.

Once the researchers understood how ureters normally find their way to the bladder, they examined mouse models with urinary tract malformations to begin to understand why they occurred. The mice they studied were genetically altered to lack retinoic acid receptors, which prevents them from being able to use vitamin A, an essential nutrient required for the formation of most embryonic tissues and organs.

Scientists have known since the 1950s that the lack of vitamin A during development leads to kidney defects. The mice without retinoic acid receptors have urinary tract abnormalities similar to those seen in humans, including having small and abnormally formed kidneys and no connections between the ureter and the bladder.

Prior research by Dr. Mendelsohns' group revealed details about how vitamin A was important for normal kidney development. At the time, she and her team found vitamin A was key to activating expression in the kidney of the Ret gene, which codes for an enzyme that adds phosphate to the amino acid tyrosine and plays a role in subcellular communication. Loss of Ret expression was the major cause of kidney abnormalities in the mice without retinoic acid receptors.

In the new study, the researchers found vitamin A and the Ret gene were also important for making normal connections between the ureter and the bladder. Kidney formation begins before the bladder and the ureter connect, Dr. Mendelsohn explains. If a mutation exists either in the retinoic acid receptor or Ret genes, kidney formation and events that occur subsequently, such as forming the ureter-bladder connection, are disturbed.

"The same genes are used at different times and in different places during urogenital tract formation, suggesting an explanation for the complexity of urinary tract malformations," Dr. Mendelsohn says.

The group also showed that restoring Ret expression into their mutant mice could rescue proper kidney development and ureter connections to the bladder. They used genetics to introduce into the mice lacking retinoic acid receptors a Ret gene with a different promoter, the regulatory region that turns on genes by responding to particular proteins. These so-called "rescued mice" were not dependent on signals derived from vitamin A activation and had normal development of urogenital organs.

Further research, Dr. Mendelsohn says, will help identify other genes controlled by vitamin A that are important for the development of the excretory system.

The National Institute of Diabetes and Digestive and Kidney Diseases and the New York Academy of Medicine supported this research.