Vitamin A activates gene to guide kidney development
Failure to activate ret gene may explain effect of vitamin A deficiency on kidney development
Vitamin A deficiency during fetal development and mutations in ret, the gene that encodes an enzyme called a receptor tyrosine kinase, are associated with kidney malformations in mice and humans. A new study by Cathy Mendelsohn, M.D., Ph.D., assistant professor of urology, and colleagues at Columbia University College of Physicians & Surgeons and University of Wisconsin-Madison demonstrates that vitamin A directs kidney development by turning on the ret gene. Says Dr. Mendelsohn, "ret is a major target of vitamin A. Our work links these together, and emphasizes how dietary vitamin A is absolutely critical for making the kidney in the mouse." Because some human kidney malformations are linked to disease susceptibility, the authors of the paper in the January issue of Nature Genetics underscore the need for pregnant women to pay careful attention to their vitamin A intake.
Proper development of the kidney requires two-way signaling between tissues. One gene that is essential to this communication is ret. Mutations in ret are known to cause cancer and malformations of the kidney and other organs. A derivative of vitamin A, retinoic acid, also is an important developmental signal. Previous work by Dr. Mendelsohn and colleagues showed that retinoic acid receptors (RARs), the proteins required to bind and respond to retinoic acid signals, are necessary for proper kidney development. Kidneys of mouse embryos lacking RARs were small and malformed; they were missing a special growth zone where new functional units, or nephrons, are added on to the growing kidney, and had a smaller than normal number of the structures that achieve the kidney's essential filtering function. They also had abnormally low levels of ret expression, suggesting an important connection between the two signaling proteins.
In the new paper, Dr. Mendelsohn and others showed in the mouse embryo and cultured embryonic mouse kidney that depriving the fetus of vitamin A could drastically reduce the amount of ret in the developing kidney tissues and also disrupt formation of kidney structures. Deleting the RAR gene, presumably necessary for vitamin A action, had similar effects. In transgenic mice that had the ret gene always turned on, however, kidney development was largely normal, even in mice lacking genes for the RAR. Because ret on its own is sufficient to trigger formation of kidney structures that normally require the RAR receptor, this result strongly suggests that vitamin A and the RAR normally direct kidney development by turning on the ret gene.
The vitamin A-RAR signal appears to be necessary to prompt branch formation in an embryonic structure called the ureteric bud. "The number of these branches is related to the number of nephrons formed," says co-author Dr. Frank Costantini, professor of genetics and development at Columbia University College of Physicians & Surgeons. While branching is impaired in mice lacking the RAR, mice transgenically altered to always produce ret show normal branching even without the RAR. Because Dr. Mendelsohn and colleagues found ret produced in ureteric bud cells, which are spatially separated from RAR-containing cells, the authors conclude that RAR-containing cells must turn on the ret gene in the ureteric bud by triggering the secretion of some type of signal that can reach their target.
Understanding how the RAR turns on ret in the presence of vitamin A may be essential to determining the optimal vitamin A level for prenatal kidney development. Says Dr. Mendelsohn, "At lower levels, you may not make as good a kidney-you may have a reduced number of nephrons." The authors conclude that "maintaining adequate levels of maternal vitamin A during gestation may be an important requirement for generating optimal numbers of nephrons in the fetal kidney."
Dr. Mendelsohn suggests that inadequate vitamin A levels during pregnancy may have important implications for the child's health in adulthood. "There's a hypothesis that a low number of nephrons leads to susceptibility to hypertension and other diseases later in life." Adds Dr. Costantini, "Having fewer nephrons is linked to increased susceptibility to kidney degeneration."
Columbia University Medical Center. February 2001.
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