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Mechanisms of Morphogenetic Regulation During Gastrulation

Hirsh, Glen
Thesis/Dissertation; Online
Hirsh, Glen
Desimone, Douglas
The shape of an embryo is achieved through tissue-scale morphogenetic movements. These force-dependent events are guided by adhesive, mechanical and chemical cues. During morphogenesis, the cells within a tissue adhere to their neighbors primarily through cadherin-catenin complexes and to their extracellular matrices through integrin-based focal adhesions. Mechanical forces are generated at sites of adhesion through actomyosin contractility. Not only are these contractile forces important for cell migration, but they also function in force-dependent mechanosensitive signaling pathways. One such mechanosensitive process is the fibrillar assembly of the extracellular matrix protein, fibronectin. Integrin receptors are important for attachment to the extracellular matrix as well as its fibrillar assembly. This force-dependent process requires cadherin-catenin adhesive complexes and actomyosin contractility. One catenin found at these adhesions, plakoglobin (also called γ-catenin), mediates the attachment of actin stress fibers to the cytoplasmic tails of classical cadherins through interactions with actin-binding proteins. In Xenopus gastrulae, plakoglobin has been identified as an essential member in the force-induced collective migration of the mesendoderm tissue. In Chapter 2 of this thesis I present data indicating that plakoglobin is required for the morphogenetic processes of convergent extension and epiboly. When plakoglobin expression is reduced, fibronectin fibrillogenesis fails as a result of cell adhesion defects. Plakoglobin morphant cells are unable to form strong attachments to cadherin or fibronectin substrates, processes that are required for assembly of the soluble dimers into fibrils. Contractile forces applied at cell adhesions function as mechanical cues that can also activate intracellular signaling pathways in neighboring cells. Mitochondrial enzymes have been found to undergo conformational changes, likely associated with changes in activity states, in response to mechanical stimuli. During the collective migration of the mesendoderm, cells within the leading edge extend broad lamellipodial protrusions that apply high traction stresses to a fibronectin substrate. In Chapter 3 of this thesis I provide evidence indicating that these protrusions contain densely packed, punctate mitochondria. The mitochondria in these protrusions are dynamic, in a high activity state, and likely coordinate the collective migration of the tissue through the localized production of ATP and purinergic signaling. The data presented in these studies focus on two different force-dependent processes in the context of morphogenesis. In addition, my work identifies plakoglobin as a regulator of fibronectin fibril assembly, which emphasizes the role of cadherin adhesion in fibrillogenesis. My work on the mesendoderm suggests that a mechanical activation of mitochondria functions in collective cell migration. Together, these findings provide a more comprehensive understanding of the morphogenetic processes involved in embryonic development as well as in the progression of diseases such as fibrosis and cancer metastasis.
University of Virginia, Department of Molecular, PHD (Doctor of Philosophy), 2017
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PHD (Doctor of Philosophy)
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