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Elucidating the role of integrin-mediated adhesion during animal morphogenesis

University of British Columbia

During the morphogenesis of multicellular organisms, cells undergo rearrangements and morphological changes to generate three dimensional structures and thus give rise to tissues and organs. Robust morphogenesis requires connections between neighbouring cells and to the extracellular environment in order to generate dynamic large-scale tissue rearrangements. Cellular adhesion to the extracellular matrix (ECM) is primarily mediated by the integrin family of adhesion receptors. Integrins are transmembrane heterodimeric receptors that bind ECM ligands extracellularly, and on their intracellular sides bind a diverse group of proteins known as the integrin adhesion complex (IAC). Integrins are involved in many fundamental biological processes and they contribute to animal development through two distinct mechanisms; first, via dynamic short-term adhesions such as those driving cell migrations and cellular rearrangements, and second via long-term stable adhesions such as those involved in tissue maintenance. Thus, the activity of integrins needs to be finely regulated during morphogenesis. In this thesis, I aim to investigate the regulation of integrins during Drosophila morphogenesis in the context of both stable long-term adhesions, and short-term dynamic adhesions. First, I investigate the role of talin, a large scaffolding protein which provides a direct link between integrins and the actin cytoskeleton, in the context of muscle development during fly embryogenesis. Importantly, talin also functions as an integrin regulator by regulating the affinity of integrin for its extracellular ligands, a process known as inside-out activation. I describe results suggesting that the talin head domain reinforces and stabilizes the integrin adhesion complex by promoting integrin clustering in a mechanism distinct from its role in supporting inside-out activation. Secondly I investigate a process known as dorsal closure (DC), an integrin-dependent dynamic morphogenetic event during fly embryogenesis that is characterized by rapid tissue movements, and the generation of biophysical forces. I find that integrins play a key role in regulating cell behaviours critical for DC via two main mechanisms: through modulating the localization of cell-cell adhesion proteins, and by regulating the dynamics of force-generating actomyosin machinery. Overall, my work highlights the diverse functions of integrins during development, and necessity for fine-tuning of their regulation during morphogenesis.

Text

2016-10-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/57597

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/