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Program in Cellular Regulation and Metabolism

This program encompasses seven groups in the Laboratory of Gene Regulation and Development (LGRD) that apply a combination of genetics, cell biology, biochemisty, and structural biology to elucidate the molecular basis of processes fundamentally important in cellular metabolism and regulation, and in animal development. Three of the seven groups study transcriptional and translational control of gene expression and the transposition of retroelements in budding or fission yeast. Two groups employ the fruit fly Drosophila to investigate molecular mechanisms in animal development, including the molecular basis of neuronal connection specificity in the visual system and mechanisms of cell signaling by TGF -beta factors. The aneuran Xenopus laevis serves as a model system for the work of the remaining two groups, focused on chromosome segregation and cell cycle control and transcriptional programming of organ development during metamorphosis.

Mary Dasso’s Section on Cell Cycle Regulation uses a variety of metazoan systems, including Xenopus laevis egg extracts, to study mitotic roles of the Ran GTPase, the nuclear pore complex (NPC) and the SUMO family of ubiquitin-like proteins. These pathways work in an interconnected manner to assure the accurate segregation of chromosomes during mitosis. In the past year, members of the group documented novel roles for both the SUMO pathway and NPC components in the assembly and function of mitotic kinetochores. Particularly the latter aspects of kinetochore function are regulated through Ran.

The Section on Protein Biosynthesis, headed by Thomas Dever, is characterizing the structure and function of several translation initiation factors and the molecular principles of kinase-substrate recognition by the stress-responsive eIF2a kinases. The group recently reported that rapid evolution of the kinase domain of the eIF2a kinase PKR alters the sensitivity of the kinase to poxvirus inhibitors, identified functionally important contacts between the GTPase translation factor eIF5B and the body of the small (40S) ribosomal subunit, and demonstrated that the hypusine-containing protein eIF5A promotes translation elongation.

The Section on Nutrient Control of Gene Expression, headed by Alan Hinnebusch, studies the transcriptional and translational control of amino acid biosynthetic genes. Recently, the group provided evidence that interaction of translation initiation factor 2 with the regulatory subunits of its guanine nucleotide exchange factor, eIF2B, is conserved in archaea, providing new structural insights into the eIF2B-eIF2 complex. Members of the group identified an inhibitory network of hydrophobic residues in the kinase domain of Gcn2 that prevents its phosphorylation of translation initiation factor 2 in amino acid–replete cells. They showed that a cascade of kinases that phosphorylate the C-terminal domain (CTD) of RNA polymerase II operates in the transition from initiation to elongation of transcription. They discovered a novel connection between the status of protein sorting at the late endosome and the efficiency of transcriptional activation in the nucleus.

The Unit on Neuronal Connectivity, headed by Chi-Hon Lee, investigates the development and function of color-vision circuits in Drosophila. His group found that TGF-beta/Activin signaling plays a key role in coordinating mutual synaptogenesis between R7 photoreceptors and Dm8, their target neurons. His group is also developing genetic tools to dissect color-vision circuits. By selectively inactivating or restoring the synaptic activity of various types of neurons, his group recently demonstrated that spectral preference to UV and green light is mediated by two distinct types of second-order interneurons.

Henry Levin heads the Section on Eukaryotic Transposable Elements, which analyzes LTR retrotransposons and the integration of their cDNA into the chromosomes of host cells. Recently, the laboratory demonstrated that Tf1 integration occurs primarily at promoters and that this mechanism is mediated by transcription factors. In the case of the fbp1 promoter, the group found that integration occurs at the binding site for the transcription factor Atf1p and that the factor is required for integration. This year, the group used ultra-high throughput sequencing to generate a saturating map of sites targeted by Tf1. Importantly, they found that integration occurred preferentially at promoters that are induced by environmental stress.

The Unit on Cellular Communication, headed by Mihaela Serpe, investigates molecular mechanisms that regulate cellular signaling during development, using the Drosophila system. The group focuses on signaling by TGF-beta factors and on genes that modulate the function and distribution of the signaling ligands in time and space. Formation of BMP morphogen gradients requires opposing actions of Tld/BMP-1 enzymes and their substrate Sog in Drosophila and Chordin in vertebrates. The group showed that several residues at the processing site are responsible for making Sog (and not Chordin) dependent on BMP binding for its processing and degradation. Mutations of these residues render Sog independent of co-substrate for processing by Tld in vitro and reduce the in vivo range of the Sog-BMP complexes in Drosophila embryos, altering the shape of the BMP morphogen gradient.

The Section on Molecular Morphogenesis, headed by Yun-Bo Shi, studies the gene-regulatory mechanisms controlled by thyroid hormone (TH) receptor (TR) that establish the developmental program of metamorphosis. The laboratory recently showed that the level of TR-binding coactivators regulates the rate of metamorphosis progression, and they revealed the origin of the TH-induced adult intestinal epithelial stem cells. The group also showed that a TH-induced matrix metalloproteinase regulates apoptosis via two different mechanisms in different organs during metamorphosis.

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