"Catch-up" Growth Signals Revealed

The results, published in the Feb. 15 issue of the journal Development, could lead to better understanding of why babies who undergo catch-up growth are at higher risk in later life for diabetes, cardiovascular disease, obesity and other health problems.

“Catch-up growth is a widespread phenomenon in the animal kingdom, from humans down to little fish and worms,” said Cunming Duan, U-M professor of molecular, cellular and developmental biology. “But biologists have known very little about the molecular signals that coordinate this phenomenon.”

Duan and co-workers suspected that a group of hormones called insulin-like growth factors (IGFs)—known to be important in normal growth and development and also implicated in cancer and aging—might be involved. Like other peptide and protein hormones, IGFs work by binding to receptors on the cells they target. The binding then sets off a cascade of reactions that ultimately direct the cell to do something.

“Since we were dealing with a type of growth, it made sense to look at the main growth regulators,” Duan said.

Also, in research published in 2010, Duan's group found that altering oxygen levels in muscle cells changed the chemical signal of IGF. Knowing that catch-up growth can be triggered by changing oxygen levels, the researchers reasoned that IGF might mediate the process.

Using zebrafish as a model system, Duan's group did a series of experiments. First, they simply monitored growth and IGF signaling in fish embryos grown in water in which the oxygen concentration was reduced for a time and then restored. As expected, growth was suppressed when oxygen was low, but the fish caught up with a growth spurt when oxygen was restored to normal levels. Interestingly, IGF signals changed in concert with oxygen levels.

Next the researchers repeated the low-oxygen, normal-oxygen experiment with a different twist: They blocked IGF signaling in the fish embryos, using either genetic methods or pharmacological inhibitors.

“We found that if you block IGF signaling, the animal cannot catch up,” Duan said. “From this we learned that the IGF signal is not only changing, but that the change is really necessary for the animal to catch up.”

Duan's group went on to investigate the specific biochemical pathways involved. They found that one, called the MAP kinase pathway, is critical for catch-up growth. However, it may not be the only pathway that figures in, and the specific pathway used may depend on circumstances.

“You can think of it like your route to work. Maybe you normally take I-94, but if it's blocked, you use other routes that you normally don't use,” Duan said.

In future research, Duan's group wants to explore the long-term effects of changes in the IGF-MAP kinase pathway that are related to catch-up growth.

“If we find lasting changes, we may be able to figure out ways of intervening to reduce the risk of associated health problems that develop later in life,” Duan said.

In addition to Duan, the paper's authors are postdoctoral fellow Hiroyasu Kamei, former postdoctoral fellow Yonghe Ding, former graduate student Shingo Kajimura, graduate student Michael Wells and former undergraduate student Peter Chiang.

Funding was provided by the National Science Foundation and the Japan Society for Promotion of Science Fellowship program.

Cunming Duan: www.mcdb.lsa.umich.edu/faculty_cduan.html

Developmen: http://dev.biologists.org