When Olivier Pourquié looks at the amorphous shape of a mouse embryo, he sees more than a blob of cells. He sees a biological clock that turns on every 90 minutes, setting off the cascade of events that will create the individual segments making up the spine.
Starting at the head and moving toward the tail, the growing cells pinch off a string of identical segments destined to become individual vertebrae that sprout blood vessels, peripheral nerves, and muscle. In people, defects in this segmentation process can cause vertebra and rib deformities that worsen with growth and require intricate orthopedic surgery.
Pourquié studies the genetic and developmental mechanisms that control segmentation. Plants, fruit flies, fish, chickens, and people all use some sort of segmentation of the main body axis as the basic building blocks for their bodies. In vertebrates, the repeated parts ensure that the rod-like spinal column can hunch, arch, and twist.
In studies of the chicken embryo, Pourquié and his colleagues found the first evidence that a molecular clock precisely times the beginning of the development of each new segment. Every 90 minutes, a transcription factor turns on just as a new segment forms. In mouse embryos, which Pourquié also studies, a new segment forms every 120 minutes until 65 have been added along the spine. This work validated a concept based on a mathematical model involving an oscillator, proposed about 30 years ago to explain segmentation of the developing spine.
Subsequent work by Pourquié's lab and others showed that the clockwork relies on feedback loops involving two key signaling pathways, Notch and Wnt. Pourquié and his colleagues showed that while the clock sets the pace for generating new segments, a traveling threshold of growth factors guides their spacing. Growth factors are churned out by the leading edge of cells forming the spine. The signal grows weaker as the molecules degrade and the cells making the factors move out of reach.
The molecular mechanisms underlying the clock oscillator and its role in development remain poorly understood. Pourquié plans to design fluorescent markers to visualize different genes acting at different times. He is beginning to apply microarray technology to identify new pathways in this cyclic process. And he has started a collaboration with researchers at Children's Hospital in Boston to analyze the genetic basis of congenital scoliosis in people, which is rare but runs in families who are also more prone to sporadic spinal deformities well after birth.
