My primary research interest is in the genetic determinants of intellectual disability (ID), formerly referred to as mental retardation (MR). I specifically study the roles of copy number variation and somatic structural variation in the context of a “genomic mutational burden” hypothesis of ID. This hypothesis is investigated using a combination of conventional cytogenetics methods (chromosome analysis and fluorescence in situ hybridization) and new molecular, high throughput, and high data volume, genomic technologies including single nucleotide polymorphism (SNP) arrays, gene expression microarrays, comparative genomic hybridization (CGH) arrays as well as custom targeted, whole exome, and whole genome massively parallel DNA sequencing. We perform all our own bioinformatics and are actively engaged in the development of new analysis tools to better meet our needs and those of the scientific community. Drosophila melanogaster and the well-established GAL4/UAS/RNAi system are used to evaluate candidate ID genes with the use of a validated olfaction learning technique (T-Maze). Candidate genes are derived from our extensive clinical database of patients with ID that have already undergone diagnostic chromosomal microarray testing.
The Genetics of Eukaryotic Transcriptional Enhancers
Transcriptional enhancers are DNA sequences that specify inducible, spatiotemporal patterns of gene expression at most gene loci. Several complementary results from genomic studies have shown that the majority of functional sites in a genome correspond to transcriptional enhancer sequences, thus underscoring their importance for understanding basic physiology. However, while transcriptional enhancers represent a major class of regulatory DNAs in eukaryotic genomes, the entire set of sequences that are necessary and sufficient for constructing a complex eukaryotic enhancer are not yet known.
Our laboratory is focused on using molecular biology, genomics, bioinformatics, and transgenic model systems to understand enhancer biology. A major area of focus in our laboratory is the study of how different morphogen-concentration specific responses are encoded at different loci. We are also interested in understanding the sequence-function relationship well enough to understand the complex patterns of molecular evolution occurring at enhancer sequences.
Homeostasis is a robust form of regulation that allows a system to maintain a constant output despite external perturbations. In the nervous system, homeostasis plays a critical role in regulating neuronal and synaptic activity. Yet the molecular basis of this form of neural plasticity is generally unknown. We address this problem using the fruit fly, Drosophila melanogaster. This model allows us to combine electrophysiology with powerful genetic and pharmacological techniques. The overall goal is to define conserved signaling mechanisms that direct synapses to maintain stable properties, like excitation levels.
It is generally believed that molecules controlling the balance of excitation and inhibition within the nervous system influence many neurological diseases. Therefore, understanding synaptic homeostasis is of clinical interest. This area of research could uncover factors with relevance to the cause and progression of disorders such as epilepsy, which reflects a state of poorly controlled neural function.
How does an egg become an adult? The means by which a single undifferentiated oocyte develops into a multicellular organism with numerous, intricately connected cell types is a major focus in developmental biology. Defects in the process of cell fate determination can lead to disease or death. Cell-to-cell communication is a common way that a cell (or a group of cells) is instructed to proceed down one particular developmental path versus another. One way that cells execute these instructions is through asymmetric division of a polarized mother cell, generating two daughter cells that contain different fate determinants and thus proceed down different developmental paths.C.elegans as a model for developmental geneticsSince all multicellular animals progress through development by overcoming similar developmental obstacles, the molecular mechanisms that overcome these obstacles have often been conserved during evolution. We use the nematode, Caenorhabditis elegans, to address the problem of how cell differentiation works in multicellular animals. C. elegans has many attributes that make it well-suited to study developmental biology, including excellent genetics, transgenics, and a sequenced genome. Especially important for our research, C. elegans also uses conserved cell signaling pathways to polarize mother cells and induce asymmetric divisions throughout its development.The importance of communicationThe Wnt signaling pathway regulates cell fate in many animals, including nematodes and mammals. Wnt signaling stabilizes a transcriptional coactivator called β-catenin, which then binds to TCF/LEF DNA-binding proteins and converts them into activators of Wnt target gene expression. β-catenin regulation is therefore a crucial step in the Wnt signaling pathway. β-catenin mis-regulation is associated with developmental defects and human diseases such as cancer. Wnt signaling also regulates many asymmetric divisions in C. elegans. An essential component of this pathway in C. elegans is SYS-1, which binds TCF transcription factors and upregulates transcription of Wnt target genes much as β-catenin does in other organisms. The crystal structure of SYS-1 confirms that SYS-1 has the structural hallmarks of the β-catenin family of transcriptional coactivators. SYS-1 shows a remarkable conservation of structure and function when compared to vertebrate β-catenin. We use these similarities (and the differences between the β-catenins) to dissect how β-catenins work. Other areas of interest in the Phillips lab are determining how the Wnt pathway functions in C. elegans, SYS-1/β-catenin regulation, and β-catenin evolution. These studies will help us understand the larger question of why animal cells differentiate the way they do.
Our research focuses on the evolutionarily conserved process of meiosis, using C. elegans as a model system. Meiosis enables sexual reproduction by the production of haploid gametes. A successful meiotic division relies on the formation of crossover events between each pair of homologous chromosomes. These crossover events are formed in the context of the synaptonemal complex (SC), a protein complex that bridges paired homologous chromosomes during meiotic prophase I. Hence, in the absence of a functional SC, meiosis is abrogated. Perturbation of meiosis can lead to chromosome nondisjunction, which is the leading cause for miscarriages and birth defects in humans. These observations, combined with evidence from studies of infertile patients, suggest a connection between SC dysfunction and chromosomal nondisjunction in human reproduction. In our lab we aim to discover and characterize novel genes essential for various aspects of meiosis, including genes essential for chromosome pairing, recombination, and the regulation of SC assembly and disassembly. To accomplish this goal, we are engaged in genetic screens targeted to isolate genes in these processes. This approach has already resulted in the identification of a novel class of mutants affecting SC disassembly. We combine our genetic approaches with high-resolution microscopy to investigate the role of these proteins in meiosis. These studies will result in a better understanding of the various fundamental processes unfolding in C. elegans meiosis and will lead to insights into this basic process in other organisms as well. In-depth investigation of meiosis is of central importance for progress in developing methods to prevent and treat infertility and birth defects stemming from meiotic chromosome nondisjunction in humans.
Prostaglandins are transiently acting hormones that are synthesized at their sites of action by cyclooxygenase (COX) enzymes, the targets of Aspirin and Advil, to mediate a variety of biological activities, including inflammation, sleep, reproduction, and cancer development. How do prostaglandins regulate these diverse, cellular events? To address this question we have developed Drosophila oogenesis as a new a new and powerful model for studying prostaglandin signaling. Using both pharmacology and genetics, we discovered that prostaglandins mediate Drosophila follicle development, identified the Drosophila COX1 enzyme, Pxt, and revealed that genetic perturbation of prostaglandin signaling can be used to exam the function of prostaglandins. This research on prostaglandin signaling implicates it in modulating actin/membrane dynamics, cell migration, stem cell activity, and the timing of gene expression during Drosophila follicle development. The lab is currently pursuing how prostaglandin signaling regulates actin dynamics and invasive cell migrations during Drosophila follicle development. By using a multifaceted experimental approach that combines Drosophila genetics, cell biology, live imaging, and biochemistry to we can begin to work out the mechanisms by which prostaglandins regulate these processes, and provide general insight into how prostaglandins regulate the cytoskeleton and migration at a cellular level. Such mechanisms of prostaglandin action are likely to be reutilized throughout development, including mediating the changes that occur during cancer progression and metastasis.
Major research interests in this laboratory concern the genetic control of function and development of the nervous system. Currently we focus on mutants of the fruit fly Drosophila with altered nerve excitability and deficiencies in learning behavior. The effects of single-gene mutations and their interactions in double mutants provide clues for the functional organizations of the ionic channels and second messenger pathways that govern neuronal activities and synaptic plasticity.Mutant alleles and conditional expression of transients are analyzed to elucidate experience-dependent plasticity in the development of the functional organization in the nervous system. The effects of altered nerve activity and physiological actions on the path finding, arborization, and generation of neural connectivities are determined in neuronal cultures as well as in genetic mosaics.
Our research focuses on cell-cell signaling events that lead to intracellular calcium release. We integrate in vivo image analysis coupled with molecular-genetic tools to elucidate the role of calcium-dependent signaling networks critical in developmental processes such as body plan formation and organogenesis in the zebrafish. The zebrafish model system for vertebrate developmental biology has many attributes including genetics, rapid development and translucent embryos. We defined a class of Wnt signaling ligands that modulate intracellular calcium release and are investigating the mechanisms by which this Wnt/calcium class mediates its biological effect on the developing embryo. As inappropriate Wnt signaling has been associated with a high frequency of tumors, we are also investigating spontaneous tumor formation in genetic backgrounds that disrupt the function of Wnt/calcium class ligands. Additionally, we have determined that the calcium release requires G-protein signaling. To identify potential intracellular regulators of calcium release dynamics, we are characterizing members of the regulators of G-protein signaling protein family. We have cloned and characterized a few members of the RGS family and find they have essential roles in sensory neuron and somite patterning. Due to the remarkable conservation of developmental processes and mechanisms among vertebrates, we also use zebrafish as a model for human disease and test candidate genes. Of note are studies involving retinal degeneration and Bardet-Biedl Syndrome.
Advances in molecular biology, epidemiology, quantitative analysis and developmental biology have made it possible to identify genes involved in common complex traits in humans. Our laboratory applies these tools to study birth defects and prematurity. One project includes strategies to identify and characterize genes involved in cleft lip and palate, an inherited human birth defect. We have identified several genes involved in facial development and are studying their environmental covariates and clinical impact. For prematurity, a condition that causes 3 million deaths worldwide each year, we are using large sample collections and genome wide linkage and association to study thousands of individuals for millions of gene variants to generate enormous power for gene detection. Many of our studies are carried out using large population and epidemiologic studies of children , particularly from the Philippines, Japan, Denmark and Brazil, and we work in close collaboration with investigators in these countries. The studies of prematurity require clinical, biological and bioinformatic collaboration. We are also involved in studies of the prevention and better treatment of children with these disorders. Combining our molecular and developmental expertise with studies of epidemiology and environmental causes, holds out the promise for developing a better understanding of both rare disorders and common conditions. We are now developing strategies for prevention that include manipulation of genes or gene-environment interactions to prevent the primary occurrence of these tragic disorders. Graduate students serve in leadership roles for these projects and have primary responsibility for project design, implementation and publication. We are strongly committed to providing opportunities for students in the classroom, the laboratory and in fieldwork to develop their interests and expertise in the application of genetic tools to an understanding of human disease.
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