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Academic Background

Bill Theurkauf received his BA from Brandeis University in 1980, and his PhD in Biochemistry from Brandeis in 1988. From 1988 to 1993 he was a postdoctoral fellow in the Department of Biochemistry and Biophysics at UCSF, where he was supported by fellowships from the Damon Runyon-Walter Winchell Cancer Research Fund and NIH. From 1993 to 1998, he was a member of the faculty of the Department of Biochemistry and Cell Biology at the State University of New York at Stony Brook. In September 1998, Dr. Theurkauf joined the Program in Molecular Medicine at University of Massachusetts Medical Center as an associate professor. He is currently a professor in the Program in Molecular Medicine and Director of the Program in Cell and Developmental Dynamics

RESEARCH INTERESTS

The germline transmits the genetic instructions that perpetuate species, which presents unique pressures on genome maintenance systems. We’re interested in the mechanisms that maintain the integrity of the “immortal” genome during germline development, and in the developmental consequences of defects in these mechanisms.

piRNA PRODUCTION AND FUNCTION

Transposons and transposon fragments represent approximately half the human genome. Mobilization of these elements can lead to genetic instability and disease, but may also drive evolution and generate diversity during neurogenesis. In bilateral animals, Piwi-interacting RNAs (piRNAs) silence transposons during germline development and have a critical role in maintaining the integrity of the inherited genome. Primary piRNAs bind to PIWI clade Argonaute proteins and mediate transposon silencing. These small silencing RNAs are generated from long precursors encoded by heterochromatic clusters. Most of the piRNA processing machinery, by contrast, localizes to the perinuclear nuage. We would like to understand 1) the genetic and epigenetic mechanisms that specify clusters; 2) How transcripts from the heterochromatic piRNA clusters are directed to the biogenesis machinery/nuage, and 3) how piRNAs suppress transposition.

Related publications:

Klattenhoff, C. Bratu, D, P., McGinnis-Schultz, N., Koppetsch, B. S. , Cook, H. A., and Theurkauf, W. E. (2007). Drosophila rasiRNA pathway mutations disrupt embryonic axis specification through activation of an ATR/Chk2 DNA damage response. Developmental Cell 12, 45-56.

Li, C., Vagin, V. V., Lee, S., Xu, J., Ma, , Xi, H, Seitz, H., Horwich, M. D., Syrzycka, M., Honda, B. M., Kittler, E. L. W., Zapp, M. L., Klattenhoff, C., Schulz, N., Theurkauf, W. E., Weng, Z. and P. D. Zamore (2009). In the absence of Argonaute3, Aubergine-bound piRNAs collapse, but Piwi-bound piRNAs persist. Cell 137, 509-521.

Klattenhoff, C., Xi, H, Li, C, Lee, S., Xu, J., Khurana, J.S., Schultz, N., Koppetsch, B. S., Nowosielska, A., Seitz, H., Zamore, P.D., Weng. Z. and William E. Theurkauf (2009). The Drosophila HP1 homologue Rhino is required for transposon silencing and piRNA production by dual strand clusters. Cell 138, 1137-1149. PMID: 19732946.

Khurana, J. S., Xu. J., Weng, Z. and W. E. Theurkauf (2010). Distinct functions for the Drosophila piRNA pathway in genome maintenance and telomere protection. PLoS Genetics 6, e1001246.

TRANSPOSON CONTROL AND GENOME EVOLUTION

The piRNA pathway represents an adaptive immune system that controls the activity of mobile genetic elements. This rapidly evolving genome pathogens can arise from infectious viruses and spread through both interbreeding and poorly understood horizontal transfer mechanisms. We have recently found that introduction of P element transposons activates a broad spectrum of resident transposon families, and that silencing of the invading P element and resident elements is linked to generation of new transposon insertions in piRNA clusters that are transmitted through the germline with high fidelity. These findings indicate that adaptation to transposon invasion triggers significant structural changes in genome architecture that appear to genetically enhance silencing capacity. Ongoing studies are directed at understanding how invasion of a single transposon activates resident elements, and the role of this process in chromosome evolution.

Related publication:

Khurana, J. S., Wang, J., Xu, J., Koppetsch, B., Thomson, T., Nowosielska, A., Li., C., Zamore, P. D., Weng, Z., and W. E. Theurkauf (2011). Adaptation to P element transposon invasion in Drosophila melanogaster. Cell 147, 1551-1563.

DNA DAMAGE CONTROL OF DEVELOPMENTAL PROGRESSION

DNA damage checkpoint pathways have well-established roles in control of cell division and maintenance of genome integrity. Recent studies from a number of laboratories indicate that complex developmental processes are also regulated in response to DNA damage. In Drosophila, the axes of the embryo are specified through asymmetric localization of morphogenetic RNAs in the developing oocyte. During early embryogenesis, the maternally supplied RNAs that drive initial development are degraded and the genome of the zygotic is transcriptionally activated at the maternal-zygotic transition (MZT), which represents a switch in genetic control of development from the mother to the zygote. Axis specification and the MZT are controlled by DNA damage signaling through Chk2 kinase, which functions as a tumor suppressor in humans. We would like to understand how Chk2 governs these key developmental processes.

Related publications:

Klattenhoff, C. Bratu, D, P., McGinnis-Schultz, N., Koppetsch, B. S. , Cook, H. A., and Theurkauf, W. E. (2007). Drosophila rasiRNA pathway mutations disrupt embryonic axis specification through activation of an ATR/Chk2 DNA damage response. Developmental Cell 12, 45-56.

Benoit, B., He, C. H., Zhang, F., Votruba, S. M., Tadros, W., Weswood, J. T., Smibert, C. A., Lipshitz, H. D., and W. E. Theurkauf (2009). An essential role for the RNA-binding protein SMAUG at the Drosophila maternal-to-zygotic transition. Development 136, 923-932.

Rotation Projects

Rotation Projects

Proper control of cell division and accurate chromosome segregation are fundamental to cell function and normal development. Chromosome segregation errors lead to birth defects, and abnormal cell division control is associated with essentially all cancers. A major aim of research in the laboratory is to understand cell cycle control and chromosome segregation mechanisms. We use a combination of classical and molecular genetics, high-resolution in vivo imaging, and biochemical techniques to define pathways that control the cell cycle and chromosome segregation in response to environmental insult (DNA damaging agents) and developmental queues. Rotation projects focus on the role of cell cycle checkpoint and tumor suppressor pathways during the earliest stages of embryogenesis, and cell cycle control of actin and microtubule reorganization during mitosis. Through these projects, students gain exposure of the art in vivo imaging and genetic and molecular manipulations of gene function to define pathways controlling cell division and chromosome segregation.

Embryonic Patterning

Essentially all cells are asymmetric, with structurally distinct surfaces and polarized internal organization. This asymmetry is essential to the specialized functions cells serve within complex multi-cellular organisms . A second area of interest focuses on the mechanisms that establish cellular asymmetry. In Drosophila, the embryonic axes are specified during oogenesis through the asymmetric localization of key morphogenetic molecules within the developing oocyte. We use axis specification in the fly as a model for the processes that establish cellular asymmetry. An intact microtubule network is essential to axis specification in the fly oocyte and to polarization of somatic. We hope to define the molecular functions for microtubules in establishing cellular asymmetry. We are currently using in vivo imaging techniques to directly characterize the microtubule dependent mRNA transport processes that differentiate the anterior and posterior poles of the developing oocyte. In addition, classical genetic and biochemical techniques are used to identify the microtubule motors and associated proteins that mediate mRNA movements to the oocyte poles.

One or more keywords matched the following items that are connected to Theurkauf, William
Item TypeName
Academic Article Mutations that perturb poly(A)-dependent maternal mRNA activation block the initiation of development.
Academic Article Anastral meiotic spindle morphogenesis: role of the non-claret disjunctional kinesin-like protein.
Academic Article Oocyte differentiation: a motor makes a difference.
Academic Article Behavior of structurally divergent alpha-tubulin isotypes during Drosophila embryogenesis: evidence for post-translational regulation of isotype abundance.
Academic Article Identification and characterization of mitotic mutations in Drosophila.
Academic Article DNA-replication/DNA-damage-dependent centrosome inactivation in Drosophila embryos.
Academic Article Actin cytoskeleton: putting a CAP on actin polymerization.
Academic Article Development. The message is in the translation.
Academic Article DNA-replication checkpoint control at the Drosophila midblastula transition.
Academic Article Reorganization of the cytoskeleton during Drosophila oogenesis: implications for axis specification and intercellular transport.
Academic Article In vivo analyses of cytoplasmic transport and cytoskeletal organization during Drosophila oogenesis: characterization of a multi-step anterior localization pathway.
Academic Article Recognition of a bicoid mRNA localization signal by a protein complex containing Swallow, Nod, and RNA binding proteins.
Academic Article Drosophila checkpoint kinase 2 couples centrosome function and spindle assembly to genomic integrity.
Academic Article Studies on the centrosome and cytoplasmic organization in the early Drosophila embryo.
Academic Article The Drosophila ATM homologue Mei-41 has an essential checkpoint function at the midblastula transition.
Academic Article The Drosophila SDE3 homolog armitage is required for oskar mRNA silencing and embryonic axis specification.
Academic Article Centrosomes and the Scrambled protein coordinate microtubule-independent actin reorganization.
Academic Article rasiRNAs, DNA damage, and embryonic axis specification.
Academic Article TACCing down the spindle poles.
Academic Article In vivo analysis of Drosophila bicoid mRNA localization reveals a novel microtubule-dependent axis specification pathway.
Academic Article Collapse of germline piRNAs in the absence of Argonaute3 reveals somatic piRNAs in flies.
Academic Article The Drosophila HP1 homolog Rhino is required for transposon silencing and piRNA production by dual-strand clusters.
Academic Article piRNAs, transposon silencing, and Drosophila germline development.
Academic Article Arp2/3-dependent pseudocleavage [correction of psuedocleavage] furrow assembly in syncytial Drosophila embryos.
Academic Article Kinesin I-dependent cortical exclusion restricts pole plasm to the oocyte posterior.
Academic Article Meiotic spindle assembly in Drosophila females: behavior of nonexchange chromosomes and the effects of mutations in the nod kinesin-like protein.
Academic Article Transposition-driven genomic heterogeneity in the Drosophila brain.
Academic Article Tissue-specific and constitutive alpha-tubulin genes of Drosophila melanogaster code for structurally distinct proteins.
Academic Article RISC assembly defects in the Drosophila RNAi mutant armitage.
Academic Article The cytoskeleton and morphogenesis of the early Drosophila embryo.
Academic Article Actin cytoskeleton. Through the bottleneck.
Academic Article Cytoskeletal functions during Drosophila oogenesis.
Academic Article Microtubules and cytoplasm organization during Drosophila oogenesis.
Academic Article Premature microtubule-dependent cytoplasmic streaming in cappuccino and spire mutant oocytes.
Academic Article Requiem for distributive segregation: achiasmate segregation in Drosophila females.
Academic Article A central role for microtubules in the differentiation of Drosophila oocytes.
Academic Article Mutations affecting the cytoskeletal organization of syncytial Drosophila embryos.
Academic Article Dynamic changes in microtubule configuration correlate with nuclear migration in the preblastoderm Drosophila embryo.
Academic Article Normal microRNA maturation and germ-line stem cell maintenance requires Loquacious, a double-stranded RNA-binding domain protein.
Academic Article Dynein and the actin cytoskeleton control kinesin-driven cytoplasmic streaming in Drosophila oocytes.
Academic Article Drosophila rasiRNA pathway mutations disrupt embryonic axis specification through activation of an ATR/Chk2 DNA damage response.
Academic Article grp (chk1) replication-checkpoint mutations and DNA damage trigger a Chk2-dependent block at the Drosophila midblastula transition.
Academic Article Components of the RNAi machinery that mediate long-distance chromosomal associations are dispensable for meiotic and early somatic homolog pairing in Drosophila melanogaster.
Academic Article An essential role for the RNA-binding protein Smaug during the Drosophila maternal-to-zygotic transition.
Academic Article A role for Chk2 in DNA damage induced mitotic delays in human colorectal cancer cells.
Academic Article Distinct functions for the Drosophila piRNA pathway in genome maintenance and telomere protection.
Academic Article Heterotypic piRNA Ping-Pong requires qin, a protein with both E3 ligase and Tudor domains.
Academic Article Adaptation to P element transposon invasion in Drosophila melanogaster.
Academic Article UAP56 couples piRNA clusters to the perinuclear transposon silencing machinery.
Academic Article Recurrent and recent selective sweeps in the piRNA pathway.
Academic Article Immunofluorescence analysis of the cytoskeleton during oogenesis and early embryogenesis.
Academic Article Mechanical basis of meiotic metaphase arrest.
Concept Drosophila melanogaster
Concept Drosophila
Concept Drosophila Proteins
Academic Article Antisense piRNA amplification, but not piRNA production or nuage assembly, requires the Tudor-domain protein Qin.
Academic Article The HP1 homolog rhino anchors a nuclear complex that suppresses piRNA precursor splicing.
Academic Article TEMP: a computational method for analyzing transposable element polymorphism in populations.
Academic Article Adaptive Evolution Leads to Cross-Species Incompatibility in the piRNA Transposon Silencing Machinery.
Academic Article A systems level approach to temporal expression dynamics in Drosophila reveals clusters of long term memory genes.
Academic Article Structural insights into Rhino-Deadlock complex for germline piRNA cluster specification.
Academic Article Co-dependent Assembly of Drosophila piRNA Precursor Complexes and piRNA Cluster Heterochromatin.
Academic Article Adaptive Evolution Targets a piRNA Precursor Transcription Network.
Academic Article A benchmark and an algorithm for detecting germline transposon insertions and measuring de novo transposon insertion frequencies.
Academic Article piRNA-independent transposon silencing by the Drosophila THO complex.
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  • Drosophila