The Laboratory of Molecular Genetics (LMG) pursues studies in different systems that aim to elucidate molecular-genetic mechanisms of physiological and developmental control, in particular the regulation of signalling and signal transduction cascades during development. Of note are the discoveries made by the groups of two tenure-track investigators, both working on the zebrafish, a premier vertebrate model system for the study of embryogenesis.

The group of Brant Weinstein works on vascular biology, specifically the mechanisms of vasculogenesis, the initial generation of blood vessels in the embryo, and the molecular-genetic distinctions that define arterial and venous identity. While functional redirection of veins to arteries and vice versa can take place in the organism, recent work completed by many groups, including this LMG group, indicates that there is a genetically programmed distinction between different vessels when they first arise in the embryo. Work by Dr. Weinstein and colleagues has illuminated the signalling cascade that defines arterial identity in the embryo. By using a combination of genetic, molecular, and embryological techniques, the researchers showed that vascular endothelial growth factor (VEGF) plays a major role in embryonic arterial development. VEGF is expressed under the control of hedgehog signalling in the embryo and, in turn, regulates the activity of Notch that gives the proximal signal leading to vessels with arterial identity.

Identification of the contribution of Notch signalling to vessel formation relied in part on the use of a mutation, mindbomb (mib), in which too many primary neurons are generated in the embryo as a result of deficits in the Notch signalling cascade. Ajay Chitnis’s group discovered and has studied this mutant. Notch is a signalling system of major importance in many developmental systems and plays a role in some human tumors. Dr. Chitnis and his colleagues have shown that the mib mutation disrupts a gene that encodes a so-called E3 ligase. E3 ligases are the specificity-endowing components of the ubiquitin-dependent protein modification and degradation machinery, and the mib gene product functions specifically in the Notch pathway. Chitnis and colleagues’ work represents a major advance in expanding our understanding of the important and much-studied Notch pathway and, as such, has far-reaching implications in biology.