Research explores non-genetic causes of cell defects
Early in the development of a human embryo, unique cells appear along the edge of the region that will ultimately become the central nervous system. The site where these cells originate is called the “neural crest.” The neural crest, however, is a temporary structure since these cells quickly disperse throughout the embryo along pre-determined pathways and settle into many different locations in the body. Neural crest cells migrate to the head, heart, gut, and even skin cells among other places.
What is interesting about neural crest cells is that they can differentiate into a variety of specialized cell types depending upon their ultimate destination within the developing embryo. Neural crest cells that migrate to the heart, for example, will proliferate, specialize, and ultimately contribute to the great vessels coming out of the heart. Neural crest cells that move into the gut give rise to specialized nerve cells that help the intestine function. Still other neural crest cells contribute to the eye, peripheral nervous system, and bones of the face.
Molecular mechanisms – chemical cues that selectively control cell activity at particular times – put these cells in motion and direct them toward their respective destinations and ultimate fates. When something goes wrong during the cell’s journey the result is often a severe disorder such as persistent truncus arteriosis, a rare congenital cardiovascular defect in which the pulmonary and aortic valves fail to separate completely, or Hirschsprung disease, a serious intestinal disorder that results when neural crest-derived cells fail to survive, proliferate, or migrate to the end of the bowel.
“In many cases we see both congenital heart disease and Hirschsprung disease occurring in the same individual, suggesting some common basic mechanisms,” says Dr. Robert Heuckeroth, a pediatric gastroenterologist at St. Louis Children’s Hospital, and an associate professor of pediatrics and of developmental biology at Washington University School of Medicine. While genetic inheritance plays a key role in these types of defects, Dr. Heuckeroth believes that genetics alone cannot fully explain variations in the severity of these problems or their presence or absence in families. “Based on new data, we believe that non-genetic factors such as maternal nutrition, medications and health conditions also influence the ultimate fate of neural crest cells.”
A grant from the Children’s Discovery Institute will enable Dr. Heuckeroth and his associates to identify these critical non-genetic factors that may play roles in disorders related to neural crest development. Their research could lead to interventions that will prevent or reduce the severity of these types of defects.
The grant covers a multi-year research program that starts with identifying medicines that positively or negatively affect the normal progression of neural crest cells. For this phase, the team is collaborating with Dr. Stephen Johnson, associate professor of genetics, who has developed high throughput screening techniques using zebrafish. More than 1,000 different drugs will be screened.
Compounds identified in the large-scale screen will then be tested in tissue culture experiments and ultimately in studies in mice. Mice that are genetically predisposed to Hirschsprung disease (selected as the model defect for these studies) will be used to assess interactions between genetic factors and selected compounds. “We think these interactions may play an important role in some cases,” said Dr. Heuckeroth. “And we may find that medicines that are considered safe or low risk during pregnancy may be inappropriate for expectant mothers who carry genetic mutations that predispose their child to this disease.”