Elisabeth Knust

MPI-CBG | Director

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  • Basic Research

    Cell Polarity, homeostasis

  • Biomedical Research

    Retinitis Pigmentosa

Project Description

The goal of our research is to better understand the mechanisms underlying the development and maintenance of epithelial tissues. Photoreceptors in the retina are epithelial in origin and have many features common to other epithelial cells including the functional compartmentalization of their plasma membrane. We have focussed our efforts on Drosophila photoreceptors, which are organized very similarly to vertebrate photoreceptors. Previous work from this laboratory has generated and characterized mutant alleles in evolutionary conserved genes such as crumbs, stardust, Lin7, Prominin, Eyes-shut (Spannl et al., 2017, Gurudev et al., 2014, Soukoup et al., 2013, Pocha et al., 2011, Bulgakova et al., 2010, Bachmann et al., 2008, Berger et al., 2007, Johnson et al., 2002). These mutant alleles exhibit phenotypes in retinal development and/or retinal survival. Mutations in crumbs (crb) constitute a particularly interesting disease model because they recapitulate many features of the human disease, Retinitis Pigmentosa 12 (RP12), associated with early onset blindness. All our mutant alleles constitute a genetic toolbox with a range of characterized disease phenotypes ranging from moderate to severe. This toolbox is currently applied to unravel the crosstalk between cellular processes like redox homeostasis, lipid metabolism, or membrane transport in photoreceptor survival pathways. In collaboration with Raghu Padinjat’s research group at the Lipid Center, we are investigating the relevance of Phosphoinositide-lipid signaling in the context of degeneration in crb mutant retinas.

Fig.: Retinal Degeneration in a Drosophila model for RP12: Confocal images for Drosophila head sections showing the retina and the brain labelled with Phalloidin (for Actin). Within the retina, several facets bearing photoreceptors are evident. In each facet the actin-rich microvillar apical domain of the photoreceptors is observed (boxed outline). Retinas of two mutant alleles (top and bottom) in an evolutionary conserved gene called crumbs (crb) are shown here. These two mutants exhibit varying degrees of retinal degeneration when placed in constant light. At day 7, as compared to day 1, there is a progressive loss of the apical domain (boxed outline). These alleles constitute a genetic model for human Retinitis Pigmentosa (RP12), which are caused by mutations in CRB1. These genetic tools will be applied to better understand disease mechanisms.

  • Collection of Lipid Center relevant Publications

    Lehmann M, Knust E, Hebbar S. Drosophila melanogaster: A Valuable Genetic Model Organism to Elucidate the Biology of Retinitis Pigmentosa. Methods Mol Biol. 2019;1834:221-249

    Spannl S, Kumichel A, Hebbar S, Kapp K, Gonzalez-Gaitan M, Winkler S, Blawid R, Jessberger G, Knust E. The Crumbs_C isoform of Drosophila shows tissue- and stage-specific expression and prevents light-dependent retinal degeneration. Biol Open. 2017 Feb 15;6(2):165-175

    Nemetschke L, Knust E. Drosophila Crumbs prevents ectopic Notch activation in developing wings by inhibiting ligand-independent endocytosis. Development. 2016 Dec 1;143(23):4543-4553