While difficult to single out individual pieces of work (they are all important!), below are some of what one could consider to be our more significant contributions.
- We have defined the subunit composition of the mammalian cytoplasmic dynein-2 complex; this work highlighted a potentially important asymmetry with regard to the dynein-2 intermediate chains: WDR34 and WDR60 are both present within the same complex. Furthermore, our work identified TCTEX1D2 as a unique dynein-2 light chain strongly implicating it as a candidate ciliopathy gene (Journal of Cell Science, 2014).
- The lab defined a mechanism for functional coupling of COPII-coated membranes to the microtubule cytoskeleton, and provides intriguing insights into the control of formation and motility of transport carriers (Nature Cell Biology, 2005).
- The lab was among the first to identify a metazoan homologue of the COPII complex protein Sec16 (Traffic, 2006). Sec16 is essential for ER-to-Golgi traffic and it is responsible for defining the sites at which the COPII complex assembles on the endoplasmic reticulum membrane, thereby playing a major role in organization of the downstream functional architecture of the secretory pathway in metazoan cells (Journal of Cell Science 2009 and 2010).
- We showed that efficient COPII assembly is essential for efficient extracellular matrix secretion. We extended our use of zebrafish and have developed this work to provide significant insight into the role of the ER export event in tissue development (Journal of Cell Science 2012 and Biology Open 2013).
- We showed that in vitro models of epithelial cyst formation require ongoing matrix secretion for morphogenesis: exogenous extracellular matrix is on its own not sufficient (Journal of Cell Science 2012). This is highly significant as these 3D culture models, embedded in exogenous matrix (such as Matrigel™ or Geltrex™) are widely used as model of cell polarity and 3D cell organization.
- We developed LG186, a selective chemical inhibitor of GBF1 function at the ER/Golgi interface (Traffic, 2010). This was interdisciplinary project funded through a BBSRC “Selective Chemical Inhibition” grant. the widely used drug brefeldin A inhibits multiple large Arf-GEFS including GBF1, BIG1, and BIG2. LG186 is selective for GBF1. While similar to Golgicide A (also selective for GBF1 and published as LG186 was in development), LG186 has the advantage of working on cell types that are resistant to both brefeldin A and Golgicide A, notably canine cells.
- Our microtubule-motor work has also made major contributions to our understanding of endosomal organization and function (in collaboration with Pete Cullen, Nature Cell Biology 2007, Developmental Cell, 2009, Journal of Cell Science, 2013).
- Our recent work on ciliogenesis has defined a role for the transmembrane Golgi matrix protein, giantin, in the formation and normal function of primary cilia. Cilia are sensory organelles extend from nearly every cell in the human body. The ability of cells to sense and respond to environmental signals during embryonic development, as well as later in life, depends on primary cilia. Our data show that giantin controls the localization of a motor protein dynein-2 to the base of the cilium. Dynein-2 is known to be required for the formation and function of cilia. Giantin is localized to the Golgi apparatus, a central sorting station for newly synthesize proteins in the cell. This is the first time that a transmembrane protein from the Golgi has been shown to be involved in cilia formation. This work was a collaboration with Chris Westlake’s lab at the National Cancer Institute in the USA and Hiroetsu Suzuki’s lab at the Laboratory for Veterinary Physiology at the Nippon Veterinary and Life Science University in Japan.
- We have also recently submitted for publication our work on the dynein-2 complex following up on our 2013 paper. More details will be posted soon.
- Our undergraduate project students also regularly make important contributions to our work, none more so than this from Rachel, Izzy, and Niamh last year.