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Open Access Publications from the University of California

Scholarly Works (20 results)

  • Article
  • Peer Reviewed
UC Santa Barbara Previously Published Works (2019)
During evolution, ubiquitin ligases increased in number with increasing nervous system complexity. Recent work shows that proper brain development, cognitive ability, and social behavior in mice require the ubiquitin ligase TRIM67. The work illuminates how general regulators like ubiquitin promote specific functions such as nervous system wiring during development.
    Cover page: TRIMing Neural Connections with Ubiquitin
    • Article
    • Peer Reviewed
    UC Santa Barbara Previously Published Works (2016)
    Border cells are a cluster of cells that migrate from the anterior tip of the Drosophila egg chamber to the border of the oocyte in stage 9. They serve as a useful model to study collective cell migration in a native tissue environment. Here we describe a protocol for preparing ex vivo egg chamber cultures from transgenic flies expressing fluorescent proteins in the border cells, and using confocal microscopy to take a multi-positional time-lapse movie. We include an image analysis method for tracking border cell cluster dynamics as well as tracking individual cell movements.
      Cover page: Live Imaging of Border Cell Migration in Drosophila
      • Article
      • Peer Reviewed
      UC Santa Barbara Previously Published Works (2017)
      Apoptosis is a form of programmed cell death that is carried out by proteolytic enzymes called caspases. Executioner caspase activity causes cells to shrink, bleb, and disintegrate into apoptotic bodies and has been considered a point of no return for apoptotic cells. However, relatively recent work has shown that cells can survive transient apoptotic stimuli, even after executioner caspase activation. This process is called anastasis. In this Q&A, we answer common questions that arise regarding anastasis, including how it is defined, the origin of the name, the potential physiological consequences, molecular mechanisms, and open questions for this new field of study.
        Cover page: Q&A: Cellular near death experiences—what is anastasis?
        • Article
        • Peer Reviewed
        UC Santa Barbara Previously Published Works (2018)
        Today's political climate can seem hostile to science. Alternative facts, climate change denial, and relabeling of actual news as fake news are discouraging phenomena for sure. But these trends make it more important than ever to engage our politicians. Take heart! There is something you can do. You can show your representatives firsthand the amazing things you do, evidence of the economic engine that your activities generate, and the real people behind the discoveries. I did, and it was fun. We invited our congressman to the University of California, Santa Barbara (UCSB), and he accepted! For 2 hours, we explained and demonstrated efforts to cure blindness using stem cells, the medical implications of the discovery that cells can recover from the brink of death, a mosquito lab striving to eliminate insect-borne disease, and an Alzheimer's disease laboratory. Salud Carbajal peered through a microscope and met real scientists. Before his visit, he did not know what a postdoctoral fellow was, much less what stem cells look like. When he left he knew our names, how much money we bring into his district, and how important National Institutes of Health funding and international mobility are to our enterprise. Although I live in the United States, this approach should also apply to other democratic countries. If each of us converts one representative into a science champion, we can change the world.
          Cover page: Invite your representative to work. Change the world. Here’s how.
          • Article
          • Peer Reviewed
          UC Santa Barbara Previously Published Works (2020)
          During embryonic development and cancer metastasis, migratory cells must establish stable connections with new partners at their destinations. Here, we establish the Drosophila border cells as a model for this multistep process. During oogenesis, border cells delaminate from the follicular epithelium and migrate. When they reach their target, the oocyte, they undergo a stereotypical series of steps to adhere to it, then connect with another migrating epithelium. We identify gap-junction-forming innexin proteins as critical. Surprisingly, the channel function is dispensable. Instead, Innexins 2 and 3 function within the border cells, and Innexin 4 functions within the germline, to regulate microtubules. The microtubule-dependent border cell-oocyte interaction is essential to brace the cells against external morphogenetic forces. Thus, we establish an experimental model and use genetic, thermogenetic, and live-imaging approaches to uncover the contributions of Innexins and microtubules to a cell-biological process important in development and cancer.
            Cover page: Integration of Migratory Cells into a New Site In Vivo Requires Channel-Independent Functions of Innexins on Microtubules
            • Thesis
            • Peer Reviewed
            UC Santa Barbara Electronic Theses and Dissertations (2023)

            Collective cell migration is crucial for development and the preferred mode of migration by metastatic tumors, but much about it is unknown. The border cell cluster in the Drosophila ovary is an ideal model for collective cell migration, as border cells migrate on and between nurse cells. The cytoskeleton is a critical regulator of cell migration. Septins, now considered the fourth cytoskeletal element, remain unexplored in collective systems. The objective of this study was to understand the functions and necessity of septins in border cell migration.

            Using RNAi, mutants, and over-expression, we investigated the impact of septins on border cell migration and cluster morphology through fixed and live imaging. We found that knocking down septins significantly impacted border cell migration and cluster morphology through detachment failure and failure to form stable forward-directed protrusions. Overexpressing septins also dramatically impacted migration, with an inverse effect on morphology. We used high-resolution Airyscan imaging paired with Tissue Cartography to generate 3D models of the surface of the cluster and measure spectral decomposition with changes in septin expression. We also created 2D binary masks of border cells and quantified morphological changes due to septin expression.

            To uncover the mechanistic role of septins in border cell migration, we tested candidates that may interact with septins. Myosin colocalized dynamically with septins, but surprisingly they do not directly influence each other. Instead, septins and myosin are independently regulated by Rho. Septins and myosin regulate border cell membrane texture and contractility to allow for proper cortical tension, protrusion formation, and migration.

              Cover page: Septins regulate border cell surface geometry, shape, and motility downstream of Rho
              • Article
              • Peer Reviewed
              UC Santa Barbara Previously Published Works (2018)
              Metastasis remains the greatest challenge in the clinical management of cancer. Cell motility is a fundamental and ancient cellular behaviour that contributes to metastasis and is conserved in simple organisms. In this Review, we evaluate insights relevant to human cancer that are derived from the study of cell motility in non-mammalian model organisms. Dictyostelium discoideum, Caenorhabditis elegans, Drosophila melanogaster and Danio rerio permit direct observation of cells moving in complex native environments and lend themselves to large-scale genetic and pharmacological screening. We highlight insights derived from each of these organisms, including the detailed signalling network that governs chemotaxis towards chemokines; a novel mechanism of basement membrane invasion; the positive role of E-cadherin in collective direction-sensing; the identification and optimization of kinase inhibitors for metastatic thyroid cancer on the basis of work in flies; and the value of zebrafish for live imaging, especially of vascular remodelling and interactions between tumour cells and host tissues. While the motility of tumour cells and certain host cells promotes metastatic spread, the motility of tumour-reactive T cells likely increases their antitumour effects. Therefore, it is important to elucidate the mechanisms underlying all types of cell motility, with the ultimate goal of identifying combination therapies that will increase the motility of beneficial cells and block the spread of harmful cells.
                Cover page: Cell motility in cancer invasion and metastasis: insights from simple model organisms
                • Article
                • Peer Reviewed
                UC Santa Barbara Previously Published Works (2018)
                Balancing cell death and survival is essential for normal development and homeostasis and for preventing diseases, especially cancer. Conventional cell death pathways include apoptosis, a form of programmed cell death controlled by a well-defined biochemical pathway, and necrosis, the lysis of acutely injured cells. New types of regulated cell death include necroptosis, pyroptosis, ferroptosis, phagoptosis, and entosis. Autophagy can promote survival or can cause death. Newly described processes of anastasis and resuscitation show that, remarkably, cells can recover from the brink of apoptosis or necroptosis. Important new work shows that epithelia achieve homeostasis by extruding excess cells, which then die by anoikis due to loss of survival signals. This mechanically regulated process both maintains barrier function as cells die and matches rates of proliferation and death. In this review, we describe these unconventional ways in which cells have evolved to die or survive, as well as the contributions that these processes make to homeostasis and cancer.
                  Cover page: Unconventional Ways to Live and Die: Cell Death and Survival in Development, Homeostasis, and Disease
                  • Article
                  • Peer Reviewed
                  UC Santa Barbara Previously Published Works (2016)
                  Collective cell migration is emerging as a major contributor to normal development and disease. Collective movement of border cells in the Drosophila ovary requires cooperation between two distinct cell types: four to six migratory cells surrounding two immotile cells called polar cells. Polar cells secrete a cytokine, Unpaired (Upd), which activates JAK/STAT signaling in neighboring cells, stimulating their motility. Without Upd, migration fails, causing sterility. Ectopic Upd expression is sufficient to stimulate motility in otherwise immobile cells. Thus regulation of Upd is key. Here we report a limited RNAi screen for nuclear proteins required for border cell migration, which revealed that the gene encoding Tousled-like kinase (Tlk) is required in polar cells for Upd expression without affecting polar cell fate. In the absence of Tlk, fewer border cells are recruited and motility is impaired, similar to inhibition of JAK/STAT signaling. We further show that Tlk in polar cells is required for JAK/STAT activation in border cells. Genetic interactions further confirmed Tlk as a new regulator of Upd/JAK/STAT signaling. These findings shed light on the molecular mechanisms regulating the cooperation of motile and nonmotile cells during collective invasion, a phenomenon that may also drive metastatic cancer.
                    Cover page: Tousled-like kinase regulates cytokine-mediated communication between cooperating cell types during collective border cell migration
                    • Thesis
                    • Peer Reviewed
                    UC Santa Barbara Electronic Theses and Dissertations (2024)

                    The microenvironment plays a central role in supporting a diverse set of cell functions ranging from cell fate decisions that specify cell lineage during early embryonic development to single-cell and organ-scale size regulation. In the past two decades, a renewed emphasis has been placed on the mechanical microenvironment and its role in healthy and disease biology.

                    In this dissertation, I describe the rheology of granular, polyacrylamide hydrogels composed of micron-scale fragments, herein referred to as microgels, and demonstrate their utility in supporting the extended imaging of the model organism danio renio (zebrafish) and for controlling the mechanical microenvironment encapsulating pancreatic ductal adenocarcinoma organoids. This work addresses two long standing challenges in the field: 1) Microgels offer an engineered embedding method that extends zebrafish embryonic imaging times by 8 compared to field standards. 2) Pancreas ductal adenocarcinoma (PDAC) organoids exhibit an emergent pulsing behavior that is enhanced in confining microgel environments, suggesting the underlying genetics of tumor cells give rise to force generating behaviors that may be assistive for adaptation to highly fibrotic tumor microenvironments in vivo.

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