When two independent people come together and interact in novel ways, it sometimes becomes love. When scientists decipher how two unrelated molecular pathways interact in unique ways in simple model systems, the finding often becomes a key to understanding complex organisms, such as flies, mice, and men.
The pathways in question are the highly conserved Ras and LIN-12/Notch systems working inside the simple worm C. elegans. The research, led by Dr. Iva Greenwald, professor of biochemistry and molecular biophysics, and her graduate student Daniel Shaye, shows how the Ras system eliminates LIN-12/Notch protein from the surface of one particular immature cell in a process termed down-regulation. They also showed that LIN-12/Notch down-regulation is necessary for that one cell to send a signal to two of its neighbors. The end result of LIN-12/Notch down-regulation and the subsequent cell-to-cell communication is that these three cells are selected to give rise to the worms' vulva.
Besides being an elegant example of developmental molecular biology, the finding, published in the Dec. 12 Nature, offers a novel mechanism that may play a role in other systems of cell fate determinationone that relies on protein elimination rather than changes in gene expression.
How a neutral cell adopts a specific fate is a fundamental question in developmental biology. The vulva of C. elegans allows researchers to dissect the molecular methodology that transforms a neutral cell into a defined one. The C. elegans vulva develops from a subset of six initially neutral precursor cells. During normal development three of these precursor cells are selected to be vulva-slated cells by the Ras and LIN-12/Notch systems, whereas the other three cells, which never see any Ras or LIN-12/Notch activity, are selected to become skin-slated.
Mr. Shaye and Dr. Greenwald showed that Ras acts to remove LIN-12/Notch from the surface of one of the vulva precursor cells by moving the protein to a compartment inside the cell, via a process termed endocytosis, where it is degraded. The investigators identified a 15-amino acid sequence in the LIN-12/Notch protein responsible for its endocytosis. The sequence includes two leucines adjacent to each other, a molecular motif implicated in endocytosis and down-regulation of membrane proteins.
They also genetically engineered worms to produce mutant LIN-12/Notch protein, which lacked the 15-amino acid down-regulation-targeting sequence, in their vulva precursor cells. This experiment showed that vulva development failed when LIN-12/Notch could not be down-regulated. Surprisingly, they found that the cell in which LIN-12/Notch would normally be down-regulated maintained its normal fate and became vulva-slated, but the neighboring cells failed to attain their normal fate and instead became skin-slated. This result suggested that elimination of LIN-12/Notch from the surface of one cell was important for that cell to be able to send a signal to its neighbors to instruct them to become vulva-slated.
The investigators now are trying to identify the molecule that binds to the LIN-12/Notch protein on the cell surface that causes the protein to move inside the cell.
The research was supported by the National Science Foundation, National Institute on Aging and the Howard Hughes Medical Institute.
Environmental pollutants in New York City, such as compounds found in car exhaust and pesticides, adversely affect fetal development, say researchers at the Columbia Center for Children's Environmental Health (CCCEH) at the Mailman School of Public Health.
In a study published in the February Environmental Health Perspectives, the researchers analyzed air and blood samples of 263 non-smoking, pregnant African American and Dominican women in Washington Heights, Central Harlem, and the South Bronx and correlated the effects of certain pollutants on the babies after birth. Dr. Frederica Perera, CCCEH director and professor of environmental health sciences at the Mailman School, led the study. Other key investigators were Dr. Robin Whyatt, assistant professor of clinical public health, Dr. Virginia Rauh, associate professor of clinical public health, and Dr. Patrick Kinney, associate professor of public health.
The women in the study wore air monitors for a 48-hour period in their third trimester and the researchers took umbilical cord blood and maternal blood samples after delivery of the baby. Using information from the air monitors, biomarkers in the blood, and epidemiological methods, the investigators obtained detailed data about exposure to environmental contaminants to assess the effects of prenatal exposures.
The investigators found that polyaromatic hydrocarbons, or PAH, which are found in emissions from car exhaust, incinerators, power plants, and tobacco smoke, were associated with reduced birth weight and smaller head circumference in babies born to African American women.
The researchers did not find any statistically significant problems in babies born to Dominican women exposed to high PAH levels. However, African American and Dominican babies with more of the pesticide chlorpyrifos in their blood had lower birth weights. Chlorpyrifos is a chemical often used in New York City schools and public housing to kill bugs.
"Our findings are of potential concern because several lines of evidence indicate that reduction in these kinds of birth outcomes may be associated with lower I.Q. as well as poorer cognitive function," Dr. Perera says.
The study is part of a larger one begun in 1998 to investigate the prevalence of childhood asthma in Northern Manhattan and the South Bronx. The bigger study is following children from birth until at least age 5 to assess their general health, breathing, cognition, and education to see if pollutants affect the well-being of urban minority children.