Nick Brown PhD
Nick is a Reader in Cell Biology, and member of the Department of Physiology, Development and Neuroscience
Molecular analysis of morphogenesis
Co-workers: Natalia Bulgakova • Alex Davies • Hannah Green •Annabel Griffiths • Sven Huelsmann • Yoshiko Inoue • Benjamin Klapholz •
Cezary Kucewicz • Aidan Maartens • John Overton • Paula Rodriguez Sanchez • Peerapat Thongnuek • Susan Tweedie • Grace Xia
Plain English: The mechanism that keeps the individual units that make up our body, or cells, attached together is known as cell adhesion. Cell adhesion is of two types. In the first type, cell adhesion proteins on the surface of one cell bind directly to similar proteins on the surface of the adjacent cell. In the second type, which is the focus of our research, cell adhesion proteins on the surface of the cell, called integrins, bind to a network of proteins outside the cell, the extracellular matrix. Extracellular matrix proteins are made by the surrounding cells, transported outside, and assembled into a stable network. In many cases this matrix forms between two layers of cells and is used to link the two together, as the integrins in each layer bind to the same intervening extracellular matrix. An example of this is the link between two layers in our skin, the epidermis and the dermis. If the adhesion mechanism is faulty, then the two layers separate, resulting in a blister. Not only do integrins need to bind tightly to the extracellular matrix, but they also must be connected to a complex of proteins within the cell, the cytoskeleton, that dictate the cell shape, like reinforcing rods within cement.
There are two general aims to our research. The first is to elucidate how integrins are connected to the cytoskeleton. The second is to discover how integrins are used in different ways in the development of an organism from a single cell, the fertilised egg. These different ways include directing cell movements around the developing embryo, permitting cells to take on special abilities, and forming stable points of strong adhesion between cell layers. As these are complex problems, we have chosen a simple animal to study, the fruit fly Drosophila, so that we have the best chance of solving them. Fruit flies use integrins in the same way as we do, as exemplified by the fact that faulty integrins in the fly also cause blisters. We aim to discover the basic mechanisms of integrin function that are shared between all animals. In future, we will be able to apply this knowledge to the treatment of medical conditions arising from defects in integrin function, which include skin blistering diseases, muscular dystrophies, neurogical disorders, and aberrant blood clotting.
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 α-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