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LABORATORY OF MOLECULAR GENETICS

Igor B. Dawid, PhD, Chief

The Laboratory of Molecular Genetics (LMG) studies the regulation of gene expression and the genetic control of developmental and physiological processes in viruses, bacteria, and invertebrate and vertebrate animals.

Robert Weisberg and his colleagues in the Section on Microbial Genetics have studied the mechanism of antitermination in bacteriophages, a process that controls gene expression at the stage of termination of transcription. They found that RNA polymerase interacts with a specific site in the transcript to accelerate elongation and thereby suppress the slow-down required for termination.

Judith Levin’s group, the Section on Viral Gene Regulation, has studied the mechanisms of reverse transcription in HIV. The role of nucleocapsid protein in HIV-1 strand transfer has been the focus of a large part of the work, which emphasizes the interaction between the protein and nucleic acid structure in initiation of DNA synthesis and in the strand transfer reaction characteristic for retroviral replication.

Michael Cashel, who leads the Section on Molecular Regulation, has studied the mechanism of general metabolic control in bacteria as mediated by the small molecule guanosine tetra/pentaphosphate or (p)ppGpp. The long-term study culminated in the solution, through a collaborative effort, of the structure of the enzyme that both synthesizes and hydrolyzes (p)ppGpp. The work yielded major insights into regulation of (p)ppGpp metabolism and of enzyme action in general.

Robert Crouch, who heads the Section on Formation of RNA, has studied RNasesH, enzymes that degrade the RNA component of RNA/DNA hybrids. He is interested in several aspects of yeast, vertebrate, and retroviral RNaseH, with a specific focus on the role of RNaseH in cellular and retroviral replication.

The Section on Gene Expression, led by Judith Kassis, is studying the mechanism of gene silencing by the Polycomb group genes (PcG) in Drosophila and the nature of DNA elements responsible for silencing. Recent work has shown that several proteins are required for functional silencing through a so-called Polycomb Response Element. Further, Kassis and colleagues discovered that the Polycomb group factor Pho and its related factor Pho-like have partly complementary and partly redundant functions in Drosophila development.

Jim Kennison, head of the Section on Drosophila Gene Regulation, studies mechanisms of transcriptional regulation in Drosophila, focusing on trans-acting regulators of homeotic genes. Genetic screens have enabled Kennison to isolate a series of regulatory genes that have fundamental roles in controlling the expression of homeotic genes. Recent work has focused on Tonalli, which is an apparent E3 ligase, a protein that modifies other proteins. Thus, protein modification is likely to be important in transcriptional control of homeotic genes.

Brant Weinstein and colleagues in the Unit on Vertebrate Organogenesis have expanded their work on the formation of the vascular system in the zebrafish. They identified the semaphorin-plexin ligand-receptor pair as critical for patterning of the trunk vasculature and determined that the zebrafish out of bounds (obd) mutant, in which vessels are incorrectly patterned, affects plexinD1. The unit has studied several other vascular mutations, including one that affects a TGF-beta class receptor, which is mutated in humans with Hereditary Hemorrhagic Telangiectasia type 2. Transgenic and imaging tools and additional mutagenic screens are undergoing development to permit study of the formation and patterning of the vascular system.

Ajay Chitnis and colleagues in the Unit on Vertebrate Neural Development are studying formation of the nervous system in zebrafish and in particular the way in which neuronal versus non-neuronal fate is determined within the neural domain of the embryo. Notch signaling is known to be critical in this determination, and the Chitnis group is using the Notch-responsive her4 promoter to create transgenic reagents for the further analysis of this signaling pathway. Additional work has focused on the role of Zic transcription factors in determining the development of the trigeminal ganglion.

Tom Sargent and his colleagues in the Section on Vertebrate Development study neural crest specification in Xenopus. The transcription factor AP-2 is important in neural crest development and plays a role in the epidermis. By using an AP-2 construct that can be activated at will, Sargent and colleagues were able to activate AP-2 target genes in a controlled manner. With the aid of DNA microarray technology, they have mounted a broad search for such target genes. One of the genes isolated in this way is now under intense study.

Using both Xenopus and the zebrafish, Igor Dawid and colleagues in the Section on Developmental Biology have focused on the regulation of the Fibroblast Growth Factor (Fgf) pathway, a signaling pathway of great importance in development and disease. They identified a feedback inhibitor, named Sef, and showed in a collaboration that human cells contain two splice variants of Sef with subtly different functions. They showed further that a second feedback inhibitor of Fgf, Map Kinase Phosphatase 3 (Mkp3), is required at a very early stage of development for normal axial patterning of the embryo.