Elisabeth Knust

The Drosophila Crumbs protein complex and its role in epithelial cell polarity and morphogenesis and prevention of light-induced retinal degeneration

Previous and current research

Epithelial tissues in multicellular organisms are characterised by a pronounced apico-basal polarity, which is manifested in the asymmetric distribution of organelles or cytoplasmic proteins, and in the differentiation of the plasma membrane into two distinct domains, the apical and the baso-lateral domains (Fig. A). Work in our group is aimed to understand the cellular, molecular and genetic mechanisms that control the establishment and maintenance of epithelial cell polarity in the fruit fly Drosophila melanogaster. Loss-of-function mutations in crumbs, stardust or bazooka lead to embryonic lethality. The mutant phenotype is characterised by the loss of cell polarity in many epithelia, followed by disintegration of epithelial structure and extensive cell death in some tissues. crumbs encodes a large transmembrane protein, with 30 EGF-like repeats and four laminin A G-domain-like repeats in its extracellular domain. The small cytoplasmic domain consists of only 37 amino acids, but nevertheless is of crucial importance for the function of the Crumbs protein. Stardust encodes a member of the membrane associated guanylate kinase (MAGUK) family, a scaffolding protein that binds to the cytoplasmic domain of Crumbs. In addition, Stardust recruits DLin-7 and DPATJ into the protein complex. Members of the Crumbs complex are localised in the subapical region, just apical to the zonula adherens, of all ectodermally derived epithelia.

In addition to their function in epithelial cell polarity, crumbs, stardust and DPATJ are also required for the development of the eye. Loss of either gene prevents the morphogenesis of the photoreceptor cells. In the adult eye, members of the complex are concentrated at the stalk membrane (see Fig. B), a region of the apical membrane between the rahbdomere and the zonula adherens, which topologically corresponds to the subapical region of epithelial cells. All three genes are essential to prevent light-induced retinal degeneration. This phenotype is reminiscent to that induced by mutations in one of the three human crumbs homologues, Crb1, which lead to Retinitis pigmentosa 12, a retinal dystrophy characterised by an early onset blindness. This similarity makes Drosophila an ideal model to study the cellular, molecular and genetic basis of this disease.

A. Epidermis of the Drosophila embryo stained with Stranded-at-Second (red) and Neurotactin (green) to label the apical and basal side,  respectively.

B. Optical section through an adult Drosophila eye stained for Crumbs (magenta) and actin (green) to label the stalk membrane and the
rhabdomere, respectively.

Future prospects and goals

We aim to understand the cellular function of the Crumbs complex for epithelial cell polarity and morphogenesis and survival of photoreceptor cells:

1. How do the members of the complex interact with each other? What is the dynamic of the complex?
2. What other proteins are recruited into the complex and what is their function?
3. What other genes control the function of the complex?
4. How does the Crumbs complex control epithelial cell polarity?
5. How does the Crumbs complex prevent light-induced retinal degeneration? 
   

About

1979: Ph.D. in Biology, University of Düsseldorf 1980-1983: Postdoctoral fellow, Institute of Clinical Virology, University Erlangen-Nuernberg 1983-1988: Assistant Professor, Institute of Developmental Biology, University of Cologne 1988-1990: Heisenberg Fellow, University of Cologne and University of Boulder, Colorado 1990-1996: Full Professor, Institute of Developmental Biology, University of Cologne 1996-2006: Full Professor and Head of the Institute of Genetics, Heinrich-Heine University, Duesseldorf 2007: Director, Max-Planck-Institute of Molecular Cell Biology and Genetics, Dresden

Selected publications

Wodarz, A., Hinz, U., Engelbert, M. and Knust, E. (1995): Expression of Crumbs confers apical character on plasma membrane domains of ectodermal epithelia of Drosophila Cell 82, 67-76

Grawe, F., Wodarz, A., Lee, B., Knust, E. and Skaer, H. (1996): The Drosophila genes crumbs and stardust are involved in the biogenesis of adherens junctions. Development 122, 951-959.

Bachmann, A., Schneider, M., Theilenberg, E., Grawe, F. and Knust, E. (2001): Drosophila Stardust is a partner of Crumbs in the control of epithelial cell polarity. Nature 414, 638-643

Johnson, K., Grawe, F., Grzeschik, N. and Knust, E. (2002): Drosophila Crumbs is required to inhibit light-induced photoreceptor degeneration. Curr. Biol. 12, 1675-1680.

Richard, M., Grawe, F., and Knust, E. (2006): DPATJ plays a role in retinal morphogenesis and protects against light-dependent degeneration of photoreceptor cells in the Drosophila eye. Dev. Dyn. 235, 895-907.

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