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Open Access Publications from the University of California

Scholarly Works (6 results)

  • Article
  • Peer Reviewed
UC San Francisco Previously Published Works (2019)
Craniofacial morphogenesis is a highly dynamic process that requires changes in the behaviors and physical properties of cells in order to achieve the proper organization of different craniofacial structures. Boundary formation is a critical process in cellular organization, patterning, and ultimately tissue separation. There are several recurring cellular mechanisms through which boundary formation and cellular organization occur including, transcriptional patterning, cell segregation, cell adhesion and migratory guidance. Disruption of normal boundary formation has dramatic morphological consequences, and can result in human craniofacial congenital anomalies. In this review we discuss boundary formation during craniofacial development, specifically focusing on the cellular behaviors and mechanisms underlying the self-organizing properties that are critical for craniofacial morphogenesis.
    Cover page: Cellular organization and boundary formation in craniofacial development
    • Thesis
    • Peer Reviewed
    UC San Francisco Electronic Theses and Dissertations (2021)

    During development, cellular self-organization by cell segregation leads to boundary formation and is critical for the organization of morphogenetic movement and tissue patterning. Signaling between membrane-bound EPHRINS and EPH receptor tyrosine kinases is essential in boundary formation, driving segregation between EPHRIN-expressing and EPH-expressing cells. Here I examine the basic cellular mechanistic drivers of EPH/EPHRIN cellular self-organization and boundary formation. Using a cell culture system to model EPH/EPHRIN cell segregation I analyzed the contact angle of cells to estimate the interfacial tension between EPHB2- and EPHRIN-B1-expressing cells. Heterotypic cell pairs exhibited increased interfacial tension relative to homotypic cell pairs. Inhibitors of actomyosin contractility significantly diminished this increase, suggesting that actomyosin contractility drives heterotypic interfacial tension. Cell segregation assays revealed that EPH/EPHRIN driven segregation is actomyosin contractility dependent. Further, atomic force microscopy showed that EPH/EPHRIN signaling results in increased cortical tension during cell segregation. Actomyosin contractility also drives increased EPHB2:EPHB2 homotypic contacts through an increase in tension away from the cell contact. Using a mouse model I demonstrated that actomyosin contractility is critical for EPH/EPHRIN cell segregation in vivo as well. Finally, I demonstrated that tissue-wide changes in cellular organization and tissue shape are driven by minimization of heterotypic contact. These data suggest a model for cell segregation and tissue organization in which Eph/ephrin signaling results in a cortical actin differential that prevents cells from making stable contacts and drives cell segregation to affect tissue morphology by modulating interfacial tension.

      Cover page: Regulation of cell contact and tissue organization by Eph/ephrin signaling
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2020)
      Morphogenesis is a physical process that requires the generation of mechanical forces to achieve dynamic changes in cell position, tissue shape, and size as well as biochemical signals to coordinate these events. Mechanical forces are also used by the embryo to transmit detailed information across space and detected by target cells, leading to downstream changes in cellular properties and behaviors. Indeed, forces provide signaling information of complementary quality that can both synergize and diversify the functional outputs of biochemical signaling. Here, we discuss recent findings that reveal how mechanical signaling and biochemical signaling are integrated during morphogenesis and the possible context-specific advantages conferred by the interactions between these signaling mechanisms.
        Cover page: Forced to communicate: Integration of mechanical and biochemical signaling in morphogenesis
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2021)
        EPH/EPHRIN signaling is essential to many aspects of tissue self-organization and morphogenesis, but little is known about how EPH/EPHRIN signaling regulates cell mechanics during these processes. Here, we use a series of approaches to examine how EPH/EPHRIN signaling drives cellular self-organization. Contact angle measurements reveal that EPH/EPHRIN signaling decreases the stability of heterotypic cell:cell contacts through increased cortical actomyosin contractility. We find that EPH/EPHRIN-driven cell segregation depends on actomyosin contractility but occurs independently of directed cell migration and without changes in cell adhesion. Atomic force microscopy and live cell imaging of myosin localization support that EPH/EPHRIN signaling results in increased cortical tension. Interestingly, actomyosin contractility also nonautonomously drives increased EPHB2:EPHB2 homotypic contacts. Finally, we demonstrate that changes in tissue organization are driven by minimization of heterotypic contacts through actomyosin contractility in cell aggregates and by mouse genetics experiments. These data elucidate the biomechanical mechanisms driving EPH/EPHRIN-based cell segregation wherein differences in interfacial tension, regulated by actomyosin contractility, govern cellular self-organization.
          Cover page: EPH/EPHRIN regulates cellular organization by actomyosin contractility effects on cell contacts
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2021)
          The periodontal complex consists of the periodontal ligament (PDL), alveolar bone, and cementum, which work together to turn mechanical load into biological responses that are responsible for maintaining a homeostatic environment. However oral microbes, under conditions of dysbiosis, may challenge the actin dynamic properties of the PDL in the context of periodontal disease. To study this process, we examined host-microbial interactions in the context of the periodontium via molecular and functional cell assays and showed that human PDL cell interactions with Treponema denticola induce actin depolymerization through a novel actin reorganization signaling mechanism. This actin reorganization mechanism and loss of cell adhesion is a pathological response characterized by an initial upregulation of RASA4 mRNA expression resulting in an increase in matrix metalloproteinase-2 activity. This mechanism is specific to the T. denticola effector protein, dentilisin, thereby uncovering a novel effect for Treponema denticola-mediated RASA4 transcriptional activation and actin depolymerization in primary human PDL cells.
            Cover page: Treponema denticola-Induced RASA4 Upregulation Mediates Cytoskeletal Dysfunction and MMP-2 Activity in Periodontal Fibroblasts
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2016)
            Cell segregation is the process by which cells self-organize to establish developmental boundaries, an essential step in tissue formation. Cell segregation is a common outcome of Eph/ephrin signaling, but the mechanisms remain unclear. In craniofrontonasal syndrome, X-linked mosaicism for ephrin-B1 expression has been hypothesized to lead to aberrant Eph/ephrin-mediated cell segregation. Here, we use mouse genetics to exploit mosaicism to study cell segregation in the mammalian embryo and integrate live-cell imaging to examine the underlying cellular and molecular mechanisms. Our data demonstrate that dramatic ephrin-B1-mediated cell segregation occurs in the early neuroepithelium. In contrast to the paradigm that repulsive bidirectional signaling drives cell segregation, unidirectional EphB kinase signaling leads to cell sorting by the Rho kinase-dependent generation of a cortical actin differential between ephrin-B1- and EphB-expressing cells. These results define mechanisms of Eph/ephrin-mediated cell segregation, implicating unidirectional regulation of cortical actomyosin contractility as a key effector of this fundamental process.
              Cover page: Unidirectional Eph/ephrin signaling creates a cortical actomyosin differential to drive cell segregation.
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