Nick Brown PhD, Reader in Cell Biology, Member of the Department of Physiology, Development and Neuroscience
Molecular analysis of morphogenesis
Cellular adhesion and communication are vital during the development of multicellular organisms. These processes use proteins on the surface of cells (receptors) which stick cells together (adhesion) and/or transmit signals from outside the cell to the interior, so that the cell can respond to its environment. Our research is currently focused on how adhesion receptors are linked with the cytoskeleton to specify cell shape and movement within the developing animal. This linkage between the adhesion receptors and the major cytoskeletal filaments contains many components, giving it the ability to grow or shrink in response to numerous signals. For example, as the cytoskeleton becomes contractile and exerts stronger force on the adhesion sites, additional linker proteins are recruited in to strengthen adhesion.
We use the fruit fly Drosophila as our model organism to discover how the complex machinery linking cell adhesion to the cytoskeleton works, and contributes to morphogenesis. We are seeking to discover how adhesion receptors form contacts of differing strength and longevity, at one point mediating dynamic attachments as the cell moves, and at another point stable connections essential for the functional architecture of the body. At these stable sites of adhesion, such as the integrin-dependent attachments of the muscles, genetic changes to intracellular proteins that work with integrins results in partial or complete loss of integrin adhesion (Fig 1). By combining quantitative imaging with genetics we are discovering the rules that govern the assembly of the integrin adhesion complex. To combine biophysical approaches with genetics, we are developing a method of primary cell culture of embryonic muscles, where we can now generate bipolar muscles with integrin adhesions at each end (Fig 2). Of particular interest are the mechanosensitive properties of cell adhesion, where acto-myosin contraction with the cell exerts force on sites of adhesion, causing the recruitment of proteins like vinculin (Fig 3) to strengthen adhesion. Cell-cell adhesion is regulated by dynamic microtubules, and we have discovered that a novel adhesion subcomplex controlled by microtubules is required to maintain the segmental boundaries that are crucial for the generation of the pattern within the embryonic epidermis (Fig 4).
• Bulgakova NA, Klapholz B and Brown NH (2012) Cell adhesion in Drosophila: versatility of cadherin and integrin complexes during development. Current Opinion in Cell Biology 24, 702-712
• Brown NH (2011) Extracellular matrix in development: insights from mechanisms conserved between invertebrates and vertebrates. CSH Perspectives in Biology
• Ratheesh A, Gomez GA, Priya R, Verma S, Kovacs EM, Jiang K, Brown NH, Akhmanova A, Stehbens SJ, Yap AS (2012) Centralspindlin and Î±-catenin regulate Rho signalling at the epithelial zonula adherens. Nature Cell Biology 14, 818-828
• Zervas CG,Psarra E,WilliamsV,Solomon E,Vakaloglou KM and Brown NH (2011) Central multifunctional role of Integrin-Linked Kinase at muscle attachment sites Journal of Cell Science 124, 1316-1327
• Delon I and Brown NH (2009) The integrin adhesion complex changes its composition and function during morphogenesis of an epithelium. Journal of Cell Science 122, 4363-4374