FlyBase, a database for Drosophila genetics and molecular biology.
FlyAtlas, where is my gene of interest expressed/enriched in the adult fly?
Drosophila Research Labs @ Stanford University that we serve:
We seek to understand the control of gene expression. Differences in gene expression underlie the tremendous variety of cell types in our bodies and account for most of the innate differences between you and me or between me and chimpanzee. These differences are encoded in the non-transcribed parts of our genome called cis regulatory elements, regions that bind proteins (in a sequence dependent manner), which regulate transcription of surrounding genes. Surprisingly, these regulatory elements can be very far away (in linear sequence) from the transcribed elements they control, frequently tens to hundreds of thousands of basepairs apart. A major direction in the lab is to understand how such long-range interactions occur, how they achieve target specificity, and how they may be reprogrammed by alterations to the genome sequence.
We believe the answers to these questions require understanding the 3-D organization of the genome. While interactions between regulatory elements and genes are long-range, they still occur only on the same chromosome (in cis) and are not known beyond the scale of a couple of megabases, suggesting physical proximity of the elements is necessary for regulation. Moreover, if a regulatory element is artificially placed directly adjacent to a new promoter that it does not normally regulate, it will typically activate transcription from that promoter, indicating that physical proximity is generally sufficient for regulation. The genome must therefore be folded in such a way to allow communication between all the sequences that need to interact and to segregate those that should not interact. What this 3-D organization looks like, how it is established, how it changes over development, and what the consequences are for the control of gene expression are all poorly understood questions, which our lab is working to answer.
My lab seeks to understand how the brain computes at the cellular and molecular level. To do this, we combine genetic approaches with quantitative imaging and behavioral studies to explore questions drawn from systems neuroscience, cell physiology, neurodegeneration and evolution. The lab addresses these questions in the context of the fruit fly visual system, where we take advantage of the exquisite precision and rich connectivity of the brain to focus predominantly on circuits that link sensation to action.
A central focus of our work concerns the mechanisms that regulate stem cell behavior. The central characteristic of adult stem cells is their long-term capacity to divide as relatively undifferentiated precursors while also producing daughter cells that initiate differentiation. Understanding the mechanisms that regulate stem cell specification and the choice between stem cell self-renewal and differentiation is crucial for realizing the potential of stem cells for regenerative medicine. We are using the Drosophila male germ line as a powerful genetic system to identify both the cell autonomous determinants and the extrinsic cell-cell interactions that govern stem cell specification, self-renewal, and differentiation. One of the great advantages of this system is that stem cells can be studied in situ, in the context of their normal support cells. Our results indicate that signals from surrounding somatic support cells specify asymmetric division of male germ line stem cells by inducing one daughter cell to self-renew stem cell identity while directing the other daughter cell to differentiate. A second focus of our work concerns how the developmental program directs cellular differentiation. Fundamental cellular functions like the cell cycle, the cytoskeleton, and the general transcription machinery are remodelled during development to give rise to specialized cell types. We investigate the mechanisms that regulate and mediate cellular differentiation during male gametogenesis in Drosophila. Our current work focuses on three areas. 1) We are investigating the mechanisms that regulate the unique program of gene expression that takes place in primary spermatocytes in preparation for the dramatic morphogenetic events of spermatid differentiation. We have discovered that both progression of the meiotic cell cycle and expression of spermatid differentiation genes are regulated by tissue specific versions of the general PolII transcription machinery. In addition, our work implicates components upstream of the Rb pathway in the control of terminal differentiation. 2) We are exploring the mechanisms that regulate remodeling of sub-cellular organelles. Our studies revealed the first known protein mediator of mitochondrial fusion, required for formation of specialized mitochondrial structures in spermatids. Our current work indicates that human homologs of the Drosophila mitofusin protein regulate mitochondrial morphology in human cells and may play a role in differentiation of heart and skeletal muscle. 3) We are dissecting the mechanisms that remodel the actin cytoskeleton and lead to localized assembly and constriction of the acto-myosin contractile machinery during cytokinesis. We have identified mutations in over 20 new genes that block different stages of contractile ring assembly and function during male meiosis. To investigate the underlying molecular mechanisms that regulate and mediate cytokinesis, we are cloning selected of these genes. Our initial results indicate that shared mechanisms involving addition of new membrane are required for both cleavage furrow constriction during cytokinesis and polarized cell elongation during later terminal differentiation.
Our group studies pancreas developmental biology and cancer biology in several models, including fruit flies, mice and humans. We have innovated methods for studying pancreas biology in these models, and discovered cellular, molecular and genetic mechanisms governing islet β-cell growth, development and function in mouse and human pancreas. Based on our findings, we have several active clinical collaborations to investigate translational implications of our work. My training in internal medicine and oncology helps frame and inform studies in my group. One goal of our work is to translate our studies into novel diagnostic and therapeutic strategies for common pancreatic disease states in humans, particularly diabetes mellitus and pancreatic cancer. I have also contributed to science education in multiple ways over the past two decades as a PI and mentor in several graduate and post-graduate training programs at Stanford and a high school program in New England. We are committed to training the next generation of biomedical researchers.
Our research is directed towards the mechanism and regulation of RNA polymerase II transcription. Transcription is the first step and the key control point in the pathway of gene expression. Transcriptional regulation underlies development, oncogenesis, and other fundamental processes. In eukaryotes the enzyme RNA Polymerase II is responsible for transcription of messenger RNA making pol’s regulation central to gene expression. We seek to reconstitute the entire process from promoter chromatin remodeling to transcript synthesis with pure proteins and nucleic acids, to solve the structures of the proteins, and to elucidate their functional interactions.
The Li lab is a new lab in the Biochemistry department and the ChEM-H institute at Stanford University. We use chemical biology to uncover biochemical mechanisms in innate immunity and, in parallel, develop therapeutic hypotheses and lead compounds. Innate immune pathways as the first line of defense against pathogens present many exciting opportunities for chemical biologists. These pathways are a rich source of novel chemistry: they involve diverse molecular patterns in pathogens, little-explored second messengers, and drugs with poorly understood mechanism. Activation of innate immunity is a proven therapeutic strategy for vaccination, viral infection, and cancer, while inhibition is a strategy for treating autoimmune diseases and sterile inflammation. To date, however, most modulators of innate immunity are broad, non-specific, and poorly characterized, such as killed bacteria, alum crystals, and steroids. The Li lab seeks to improve understanding of these pathways and facilitate the development of more precise drugs for preventing or treating specific diseases.
Animals live in dynamic environments where external conditions vary at cyclic or irregular intervals. When faced with environmental change, an individual’s physiological fitness requires its organ systems to functionally adapt. One type of adult organ adaptation is function-enhancing growth in response to increased physiological demand. In contrast to developmental growth, adaptive growth is reversible, repeatable, and extrinsically induced. However, the mechanistic origins of adaptive flexibility and responsiveness in adult tissues are largely mysterious.
The adult Drosophila midgut is a self-renewing organ analogous to the vertebrate small intestine. Common attributes including cellular physiology, anatomic layout, stem cell lineages, and fate determinants, while simplified in the fly, imply that underlying regulatory principles are likely to be shared. The midgut is a uniquely tractable model to study adaptive growth; not only can gene expression be manipulated and lineages traced at single-cell and whole-tissue levels, but complete population counts of all cell types are possible. I have found that when dietary load increases, midgut stem cells activate a reversible growth program that increases total intestinal cell number and digestive capacity. My goal is to understand how this nutrient-driven mechanism regulates stem cells to achieve lifelong optimization of organ form and function.
The long-term goal of our research is to advance experimental paradigms for understanding normal cognitive and disease processes at the level of neural circuits, with emphasis on learning and memory processes. By contrast, much current research on learning and memory concentrates on levels of organization in the nervous system that are either more macroscopic (e.g. in cognitive psychology) or more microscopic (e.g. in synaptic physiology).
Our approach combines behavioral, electrophysiological, and computational methodologies with high-resolution fluorescence optical imaging that is capable of resolving individual neurons and dendrites. By necessity, we aim to advance imaging methods so that we can examine dynamics of neuronal populations or of dendritic compartments in behaving animals. En route, we are also performing experiments on circuit properties in anesthetized animals, such as the studies that use our newly invented fluorescence endoscopes for examining hippocampal cells and dendrites in vivo.
We seek explanations that span different levels of organization, from cells to entire circuits. We work with both genetic model organisms, mice and fruit flies, and human subjects. Our research emphasizes understanding the control and learning of motor behaviors, as well as the potential application of our newly developed imaging techniques to clinical use in humans.
We study infectious diseases and look at both the physiological mechanisms that make us ill as well as those that help us recover. We want to improve the way a host clears the infection as well as endures the symptoms of the infection. Our largest effort so far has been to separate the process of clearing microbes (which we call resistance) from the illness caused by infecting pathogens (tolerance). Our future work is shifting towards the study of recovery from infections.
Our lab uses a variety of infection models; for hosts we rely upon fruit flies and mice. For pathogens we use Plasmodium chabaudi, which provides us with a mouse model for malaria. We also study a variety of bacterial pathogens that can infect fruit flies. (Burkholderia, Francisella, Listeria, Salmonella, Staphylococcus and Streptococcus species).
Mitochondria move and undergo fission and fusion in all eukaryotic cells. The accurate allocation of mitochondria in neurons is particularly critical due to the significance of mitochondria for ATP supply, Ca++ homeostasis and apoptosis and the importance of these functions to the distal extremities of neurons. In addition, defective mitochondria, which can be highly deleterious to a cell because of their output of reactive oxygen species, need to be repaired by fusing with healthy mitochondria or cleared from the cell. Thus mitochondrial cell biology poses critical questions for all cells, but especially for neurons: how the cell sets up an adequate distribution of the organelle; how it sustains mitochondria in the periphery; and how mitochondria are removed after damage. The goal of our research at the Xinnan Wang Lab is to understand the regulatory mechanisms controlling mitochondrial dynamics and function and the mechanisms by which even subtle perturbations of these processes may contribute to neurodegenerative disorders.