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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. |