Research

embryo

The research of my lab is focused on studying the early development of the spine, and finding the genetic causes of vertebral birth defects. The vertebral column derives from embryonic precursors called somites, which are formed in a process regulated by a "segmentation clock." Although we know that genes in the notch and wnt signaling pathways are involved in the segmentation clock, the regulatory machinery of this clock is not fully understood. Recent genetic analysis has shown that disruptions of notch pathway genes cause severe vertebral defects both in mouse and humans. For example, homozygous mutations in delta-like 3, a ligand in the notch signaling pathway, are found both in the pudgy mouse, which displays vertebral defects, and in the human vertebral disorder, spondylocostal dysostosis. Under the overall goal of understanding the regulation of the somite clock, we are pursuing further genetic analysis in the following complementary areas.

First, we are working to identify novel genes involved in the segmentation clock. Certain genes in the notch signaling pathway display oscillatory changes in expression that are synchronized with somite formation. We are using microarray technology to identify novel genes with oscillatory expression in mouse embryos, and to identify genes downstream of the notch pathway signaling using targeted mouse mutants. In parallel, we are also identifying genes with oscillatory expression in human mesenchymal stem cell models of the segmentation clock.

Second, we have worked to establish the International Consortium for Vertebral Anomalies and Scoliosis, a group of geneticists and orthopaedic surgeons interested in identifying the developmental origins of spinal birth defects. Our collaborative aim is to identify the genetic etiology of human vertebral disorders, including congenital scoliosis, Klippel-Feil syndrome, Jarcho-Levin syndrome, and caudal agenesis. We have developed a unique clinical database of congenital vertebral defect cases for molecular analysis, to aid us in our goal of finding the genetic and developmental causes of spinal birth defects.