In what may offer clues to birth defects, scientists at Burnham Institute for Medical Research (Burnham) have shown that retinoic acid-a metabolite produced from vitamin A (retinol)-controls the development of forelimbs but not hindlimbs, and that it is not responsible for differentiation of the parts.
Lead researcher Dr. Gregg Duester, a professor of Developmental Biology at Burnham, says that the research corrects longstanding misconceptions about limb development.
The researcher revealed that studies on mice and zebrafish had shown that retinoic acid suppresses the gene fibroblast growth factor 8 (Fgf8) during the period when forelimb budding occurs, creating a suitable environment for the creation of forelimb buds.
"For decades, it was thought that retinoic acid controlled limb patterning, such as defining the thumb as being different from the little finger. However, we have demonstrated in mice that retinoic acid is not required for limb patterning, but rather is necessary to initiate the limb budding process.
We also found that retinoic acid was unnecessary for hindlimb (leg) budding, but was needed for forelimb (arm) budding," said Dr. Duester.
Congenital birth defects of the arms, legs, hands or feet result from improper development of limb bud tissues during embryogenesis.
These processes are regulated by signalling molecules that control the growth and differentiation of progenitor cells by regulating specific genes, one of which is retinoic acid.
Dr. Duester's team have identified the genes Raldh2 and Raldh3 that are responsible for retinoic acid synthesis, and have shown that retinoic acid is only produced by certain cells at precise stages of development.
During the study, the researchers observed that mice missing the Raldh2 and Raldh3 genes, which normally die early and do not develop limbs, could be rescued by treatment with a small dose of retinoic acid.
However, the treatment stunted forelimb development, suggesting that retinoic acid is required for forelimb but not hindlimb development.
The team further experimented on zebrafish, and were able to rescue the development of the forelimb-pectoral fin-by treating retinoic acid-deficient embryos with a drug that reduces fibroblast growth factor activity. Their experiment supported the hypothesis that retinoic acid normally reduces this activity.
The researchers believe that these findings may provide a more complete understanding of the molecular mechanisms involved in normal limb development, and lead to new therapeutic or preventative measures to combat congenital limb defects, such as Holt-Oram syndrome, a birth defect characterized by upper limb and heart defects.
The study has been published online in the journal Current Biology.