Retinoic acid flunks as a master molecule.

Retinoic acid flunks as a master molecule

Two reports published this week question a dominant tenet of developmental biology -- that a relative of vitamin A serves as a master control chemical that prompts the formation of such disparate anatomical structures as fingers, legs and toes.

By implanting microscopic beads coated with retinoic acid into the limb buds of unhatched chicks, two independent groups of researchers -- one from the University of California, Irvine, and another from three Japanese universities -- have shown that retinoic acid, a metabolite of vitamin A, does not directly dictate the pattern of limb formation in developing embryos.

The studies already have stirred two deeply divided camps of developmental biologists: those who believe that a single master chemical, or morphogen, calls the shots during development, and those who believe that a subtle interplay between the embryonic cells themselves determines whether they will become part of a finger or a thumb.

"I don't think the morphogen view works," says Susan V. Bryant, head of the Irvine laboratory. Bryant believes that as-yet-unidentified molecules on the surfaces of embryonic cells enable the cells to recognize one another and grow into the precise patterns that lead to limbs and digits.

In their experiment, reported in the March 7 NATURE, Bryant's group put a retinoic acid-soaked bead under the surface of the front edge of a chick-limb bud. They removed the bead, and an hour and a half later cut a tiny wedge of tissue from next to the implant site. When the tissue wedge was grafted onto an untreated limb bud, it made the chick grow an extra set of digits.

Bryant says the effect could not be due to retinoic acid carried over in the tissue wedge, because the chemical breaks down in less than one hour. She believes instead that retinoic acid turns on a set of cells, termed the zone of polarizing activity, which then go on to choreograph development.

The Japanese team, headed by Sumihare Noji of Okayama University Dental School, reports the results of its grafting studies in the same issue of NATURE. They found that grafts taken from an area of the chick-limb bud known to be important in development do not prompt untreated limb buds to make molecular receptors for retinoic acid. Because studies show that retinoic acid causes the expression of retinoic acid receptors, Noji's team concludes that retinoic acid alone cannot cause limb development.

Jeremy Brockes, a developmental biologist from the Ludwig Institute for Cancer Research in London, says in an accompanying commentary that although the new experiments contain some flaws, they do question the role of retinoic acid as a morphogen. But he points out that gradients of retinoic acid have been found across developing limb buds, and researchers have shown that retinoic acid alone can cause newts and salamanders to regenerate amputated limbs. "It's still an open possibility that retinoic acid is responsible" for directing limb development, he says.

The new work "is not very solid," argues Gregor Eichele from Baylor College of Medicine in Houston. Eichele was one of the discoverers of the retinoic acid gradient in developing limbs, and last year he and his wife, Christina Thaller, found a second potential morphogen, 3,4-didehydroretinoic acid (SN: 7/7/90, p.15). "The only way you can find out what retinoic acid is doing is by finding out what genes it turns on," he says.

Thomas Jessell, a developmental biologist at Columbia University in New York City, terms the new studies "interesting." Jessell, who has collaborated with Eichele and Thaller, says the new reports "will make people slightly less complacent about the identity of retinoic acid as a morphogen." But he still doesn't accept Bryant's theory that cell-to-cell interactions govern development. "You have to invoke some magic to get [it] to work," he says.