Insight into the genetic pathways that drive segmentation like clockwork

Researchers at the Stowers Institute for Medical Research are gaining new insight into the molecular players involved in the process of vertebral column formation in the embryo.

A research team headed by Dr. Olivier Pourquie, currently an Associate Scientist at the Stowers Institute, were pioneers in providing evidence for an oscillator called the segmentation clock, a timing mechanism responsible for the periodic production of the somites (the precursors of the vertebrae) in the embryo. This group now reports that the Notch signaling pathway provides the backbone of the segmentation clock in the chick embryo. These findings are reported in the Jan. 12 Advance Online Publication of the journal Nature at by Dr. Pourquie and co-authors Drs. Kim Dale and Miguel Maroto, senior research associates of Dr. Pourquie and co-equal contributors to the research. The paper’s title is “Periodic Notch inhibition by lunatic fringe underlies the chick segmentation clock.”

The group discovered that one of the genes controlled by the segmentation clock, lunatic fringe , is involved in a negative feedback loop resulting in the periodic inhibition of Notch signaling. Abnormalities in this signaling loop in mice and humans can lead to severe defects in vertebral column formation and can also be linked to the development of other more widespread pathological conditions of the vertebral column such as scoliosis.

Robb Krumlauf, Scientific Director of the Stowers Institute, said, “These results are very exciting and important because components of the Notch pathway, such as Jagged, Delta 3 and Lunatic fringe have been previously associated with vertebral defects in mouse models and in human syndromes. However, the basis of these skeletal defects was previously unknown, and this discovery firmly links the problems to early patterning processes regulated by the segmentation clock. This work provides new insight into the role of segmentation in the normal development of skeletal structures and how they may go wrong in human disease.”

“While it had previously been shown that genes regulated by the segmentation clock (cyclic genes) show oscillations of mRNA levels, this is the first demonstration that the protein of a cyclic gene also oscillates in the embryo,” said the researchers in a joint statement. “Thus we suggest that the protein of the cyclic gene lunatic fringe is a crucial component of the chick segmentation clock.”

According to the Stowers Institute team, these findings are particularly interesting in light of a recent publication in the journal Science by a research team led of by Dr. Kageyama of Kyoto University. This study describes similar oscillations of the protein coded by another cyclic gene called hes1. The group showed that cultured cells, which do not belong to embryonic segmented structures, exhibit oscillations of both the hes1 mRNA and the Hes1 protein following a single serum shock in vitro.

“Remarkably these oscillations occur with the same periodicity as the ones mediated by the segmentation clock that involve lunatic fringe in the embryo,” the Stowers Institute group said. “Together, these findings suggest that the segmentation clock might be “ticking” in other cell types in addition to the precursors of the vertebral column. Therefore, these timing processes may be implicated in a wider range of developmental contexts. Revealing the mechanism and the role of the segmentation clock in the embryo remains a challenge for the future.”