Embryonic facial development subject to insult or repair longer than expected

By Wallace Ravven on March 24, 2003

The sculpting of the face during embryonic development - the physical molding that determines what we will look like - may remain open to change much longer than had been thought, according to research by UCSF scientists. While this prolonged period means the developing face has increased vulnerability to environmental insults in utero, the plasticity also provides more opportunity for repair and restoration of facial defects in utero as new diagnostic and therapeutic techniques are developed to allow earlier intervention, the researchers say.

The study revealed that facial development is not as genetically pre-determined as many had thought, but results from interactions among neighboring tissues.

In experiments with chick and quail embryos, the scientists discovered that a small region of tissue at the front edge of what in humans would be the upper lip, dubbed FEZ, controls development of the upper half of the face. They found that FEZ growth signals could influence development of this part of the face over a longer time than expected.

The research suggests that a human embryo’s facial tissues remain responsive to its immediate environment for about nine weeks, or through most of the first trimester.  Researchers had thought that human facial form was established and unalterable by about five weeks.

The new findings may explain the puzzling fact that a single kind of environmental insult, such as maternal exposure to alcohol during pregnancy, can cause a wide range of facial defects in the developing embryo. The timing of the insult may be the deciding factor, said Jill Helms, PhD, associate professor of orthopaedic surgery at UCSF and senior author on a paper reporting the research.

Helms expects the prolonged period of plasticity will allow face-saving surgeries or treatments.
“If you follow the field of in utero surgery, you can see that it’s just a matter of time before we are able to repair facial damage in the first trimester,” Helms said. “If human facial pattern is still pliable nine weeks after fertilization, then surgeons will have a larger window during early developmental stages to repair such defects as cleft lip and palate, with little or no scar tissue and far less trauma.”  When the role of the proteins that direct shaping the face is better understood, she added, “we may be able to provide the right molecule instead of using surgery to repair birth defects,” she said.

At some points in time, the cells are very responsive to their environment, Helms says. Later in development, the cells will go their programmed way.

The UCSF research is based on experiments in which facial tissue from quail embryos was transplanted onto the developing forehead of chick embryos. When the FEZ region from a young quail embryo - essentially the embryonic skin that forms the equivalent of the human upper lip - was transplanted to the forehead of an older chick embryo, a new beak formed in response to the grafted tissue. The transplanted skin instructed the underlying cells to make the cartilages and bones that normally comprise the chick’s upper beak. FEZ stands for the frontonasal ectodermal zone, and is the boundary between two different growth-promoting molecules, FgF8 and Sonic hedgehog.

The research was published online March 18 by Development, and will appear in the journal’s print version in early May. Lead authors are Diane Hu, MD, a senior research associate at UCSF, and Ralph Marcucio, PhD, a post-doctoral scientist in the Helms lab.

The team seeks to identify the proteins that are active in the FEZ and other tissues that control craniofacial development. Hu is currently carrying out experiments with chick embryos to see if she can “rescue” craniofacial birth defects by adding back growth factors that are detected in the FEZ region.

If the approach could be developed for human embryos, surgery to repair facial defects - either in utero or after the child is born - could become unnecessary.

“It could free families from enduring the stress of having children with deformed faces,” Hu says. “If we could make this work in humans, far fewer babies will be born with deformed faces.”

The scientists see the influence of the FEZ as support for the view that facial development is fairly plastic and not strictly pre-determined by the identity and location of the cells that make the cartilages and bones of the face.  However, research published by Helms and her UCSF colleague Richard Schneider, PhD, in SCIENCE in January, demonstrated that the cells that make the cartilages and bones of the face do indeed contain intrinsic species patterning information.

The researchers think that the two lines of research show that development is the result of cells “talking to each other during particular times.”
As Marcucio puts it, paraphrasing famous embryologist, Hans Spemann, “The quail skin tells the underlying chick cells to make a face, and the chick responds by making a chicken face, which is the only face it knows how to make.”

The research was funded by grants from the National Institutes of Health.

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