Genetic "Short Circuit" Leads to Cleft Palate

Scientists have identified not just a single gene but a genetic circuit, that when broken, causes cleft palate in newborn mice. The critical points of the circuit represent genes and gene products that interact with one another to direct palate formation. The "surge" that causes the circuit to break is an environmental assault in the form of steroid hormones given to the female mice during pregnancy. This is the first time that a cause-effect scenario for cleft palate has been worked out at the molecular level.

The findings may help define the genetic components of cleft palate in humans, and also explain the link between clefting and risk factors, such as stress, smoking, and certain medications, all of which are known to elevate the level of steroids in the body. The study was carried out by Drs. Michael Melnick, Tina Jaskoll, and colleagues at the University of Southern California through support from the National Institute of Dental Research, and appears in the January issue of Developmental Dynamics.

Facial clefting disorders are among the most common human birth defects. Cleft palate occurs in about one in 2,000 live births and can range in severity from a relatively minor split uvula at the rear of the mouth, to a cleft that runs the length of the hard and soft tissues that form the roof of the mouth. The more severe forms require surgery and are often associated with both psychological and physical problems, including difficulties with feeding, breathing, and speech development.

Cleft palate is thought to result from a combination of genetic and environmental factors, yet attempts to identify these components in human populations have so far produced inconclusive results. Investigators like Dr. Melnick feel that the mouse model will provide the clues that eventually unravel the mysteries of cleft palate. At present, he thinks that it is still premature to pinpoint the underlying causes of cleft palate from human studies. "It is apparent from studying complex disorders like cleft palate, that simply identifying genetic differences between healthy and affected individuals is not enough to explain the cause of the disorder," said Melnick. "We must know what products are derived from the genes in question and what other genes and molecules are affected in the chain of events that leads to the formation of the palate."

The mouse model allows investigators like Melnick and Jaskoll to tackle such questions. Much of their work has revolved around two strains of specially bred miceone strain sensitive to steroid-induced clefting, the other strain resistant. Using these mice they have now pieced together a molecular explanation for cleft palate.

The genetic circuit that they describe is similar to an old-fashioned string of holiday lights that operates only if all the bulbs are functioning properly. The investigators have identified three of the genes and gene products involved in palate formation that are the equivalent of individual bulbs in the string of lights. The clefting-susceptible mice have an overactive gene, comparable to a bulb that burns hot but still is able to complete the circuit and light up the other bulbs in the string. In these mice, the gene alters the normal activity of the other molecules in the circuit, but the palate still forms, although more slowly than in resistant mice that have a less active form of the gene. When steroids are added to the system, the effect of the hyperactive gene is amplified to the point where the circuit is broken. The function of the other molecules is altered so much that palate tissues practically stop growing and a cleft forms in the roof of the mouth.

The three key components of the circuit are the growth factor receptor IGF-IIR (hyperactive gene), the growth factor TGF-?2, and Cdk4, a protein that drives cell division. Equivalent molecules are present in humans, and a similar pathway may be responsible for human cleft palate. However as Dr. Melnick points out, the human situation may also be more complicated. "There are several tissues involved in forming the palate and they are under the direction of dozens of genes," said Melnick. "There are many potential places for things to go wrong, and the places may vary among families and racial groups. We have identified one pathway that accounts for steroid-induced cleft palate in mice, and provides some promising targets to focus on in human population studies."

The research team consisted of Drs. Michael Melnick, Haiming Chen, and Tina Jaskoll from the Laboratory for Developmental Genetics, University of Southern California, and Drs. Susan Buckley and David Warburton from the Department of Surgery, Childrens Hospital of Los Angeles.