Planar cell polarity signaling: a mechanism for cellular polarization.
Epithelial cells are polarized in multiple ways. Apical-basolateral polarity (perpendicular to the plane of the epithelial sheath) enables a cell to directionally transport molecules across a cell layer (e.g. in the gut, kidney and glands) and selectively secrete extracellular matrix components to form a basal lamina. To perform many of their functions, epithelia frequently also have to be polarized within the plane of the epithelium. The latter polarization is commonly referred to as epithelial planar cell polarity (PCP) or tissue polarity and allows a cell to form structures that require not only positional, but also vectorial information.
The cellular consequences of PCP signaling range from coordinated organization of cytoskeletal elements in single cells to complex migration of groups of cells. Examples of PCP in vertebrates can be very obvious, as in the ordered arrangement of scales on fish, feathers of birds, and hairs of mammalian skin. Less visible examples are the cilia of the respiratory tract and oviduct as well as the stereocilia of the sensory epithelium of the organ of Corti in the vertebrate inner ear. Aberrant PCP of the sensory epithelium in the organ of Corti leads to deafness. Furthermore, the complicated movement of mesenchymal cells during gastrulation (called convergent extension) that leads to the elongation and thinning of the body axis also depends on correct PCP signaling.
PCP signaling is, however, best studied in Drosophila melanogaster, mainly because of the versatility of the fly as model system. In Drosophila, PCP can easily be seen on several external adult structures such as the bristles on the thorax or the precisely aligned hairs on wing cells. In addition, the facet eye also shows characteristics of PCP with its precise arrangement of each building block, the ommatidium, with respect to each other and the general axes in each eye. Genetic and molecular studies in Drosophila led to the identification of a signaling network – the non-canonical Frizzled-PCP pathway – directing PCP establishment. In recent years it has become apparent that the PCP signaling module is highly conserved from insects to ascidians and mammals and is one of the most exciting topics of developmental biology today.
Interests of the lab:
Due to the available tools and the possibility to use a combination of genetic and biochemical approaches, Drosophila is ideally suited to further dissect the PCP pathway and define its relationship to the cytoskeleton.
My lab is particularly interested in how the Fz-adapter protein Dsh is regulated by phosphorylation. We have identified candidate kinases and a phosphatase in a systematic molecular screen based on RNAi. Current projects further address the functional relevance of these kinases in vitro and in vivo using genetic and immunohistochemical tools.
We also study two additional kinases, Nemo and Rho kinase that have previously been shown to be required for the migration aspect of PCP establishment (and – in case of Rock – also for tumor cell migration). We have systematically identified targets of Nemo and Rock and use genetic and molecular approaches to integrate these substrates into the PCP signaling pathway and cell migration in general.
It is our goal to use Drosophila as model system to address fundamental questions that are relevant for diseases and development in general.
Jenny, A., Mlodzik, M. Planar cell polarity signaling: a common mechanism for cellular polarization. (2006). Mt Sinai J Med., 73(5), 738-750.
Jenny, A., Darken, R. S., Wilson, P. A. & Mlodzik, M. (2003). Prickle and Strabismus form a functional complex to generate a correct axis during planar cell polarity signaling. EMBO J. 22, 4409-4420.
Das, G., Jenny, A., Klein, T.J., Mlodzik, M. (2004) Diego interacts with Prickle and Strabismus/Van Gogh to localize planar cell polarity complexes. Development 131, 4467-4476.
Simons, M., Gloy,J., Ganner, A., Axel, B., Bashkurov, M., Krönig, C., Schermer, B., Benzing, T., Cabello, O., Polok, B., Driever, W., Jenny, A., Mlodzik, M., Obara, T., Walz, G. (2005) Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat. Genet. 37(5), 537-543.
Jenny, A., Reynolds-Kenneally, J., Das, G., Burnett, M., Mlodzik, M. (2005). Diego and Prickle regulate Frizzled-planar polarity signaling by competing for Dishevelled binding. Nat. Cell Biol. 7(7), 691-697.
Ciruna, B., Jenny, A., Lee, D., Mlodzik, M., Schier, A. (2006) Planar cell polarity signalling couples cell division and morphogenesis during neurulation. Nature 439, 220-224.
Jenny, A., Hachet, O., Zavorsky, P., Cyrklaff, A., Weston, M.D.W., St Johnston, D., Erdely, M., Ephrussi, A. (2006). A translation-independent role of oskar RNA in early Drosophila oogenesis. Development 133, 2827-2833.
Klein, TJ., Jenny, A., Djiane, A., Mlodzik, M. (2006). CKIɛ/discs overgrown Promotes Both Wnt-Fz/β-Catenin and Fz/PCP Signaling in Drosophila Curr. Biol. 16(13), 1337-1343.
Moeller, H., Jenny, A., Schaeffer, HJ., Schwarz-Romond, T., Mlodzik, M., Hammerschmidt, M., Birchmeier, W. (2006). Diversin regulates heart formation and gastrulation movements in development. PNAS, 103(43),15900-15905.