Prof. Dr. Leena Bruckner-Tuderman

Signalling mechanisms regulating epidermal polarity, proliferation and motility

Outside-in signalling, i.e. transfer of information from the microenvironment into the cell, is pivotal for regulating the polarity, adhesion, proliferation and motility of epithelial cells in the skin, the mucous membranes and other organs. The processes are mediated by integrins, other transmembrane receptors and their ligands, and aberrant signalling is associated with human diseases and animal pathology.  We are interested in the molecular and cellular disease mechanisms leading to the symptoms, such as skin blistering. As examples, three skin components are addressed, which are involved at different levels of signal transmission from the environment into the cell: 1) the intracellular kindlins, which mediate the attachment of the actin cytoskeleton to the plasma membrane and contribute to integrin mediated cellular processes; 2) the epithelial cell-matrix receptor, collagen XVII, which plays a significant role in keratinocyte adhesion and motility;  3) the basement membrane protein and ligand of cell receptors, collagen VII.  The work aims at determining the role of these marker molecules for epithelial signalling pathways under normal and pathological conditions. Genetic approaches using spontaneously occurring mutations in patients with blistering skin diseases or transgenic mice are combined with siRNA / gene transfer techniques in order to dissect the signalling cascades involved in the regulation of cell shape, adhesion, polarity, proliferation and motility. Expression arrays, quantitative proteomics (SILAC labelling) and phosphoproteomics are employed to compare signalling cascades in cells from normal and pathologically altered tissues. Currently we are initiating the analysis of synthetic microenvironments for cell signalling in the skin in vitro, with the goal of desing and synthesis of artificial extracellular matrices for use in regenerative medicine and novel therapeutic approaches for human diseases. The signals will be modulated by constructing synthetic matrices with different macro-/micromolecular compositions, varying liquidity and porosity for cultured cells and reconstructed skin. These applications will improve our understanding of the normal adhesion, differentiation, and motility of epithelial cells, phenomena essential for both development and regeneration, as well as pathological processes including carcinogenesis.

10 selected publications:

• RhoA activation by CNFy restores cell-cell adhesion of kindlin 2-deficient keratinocytes skin equivalents.
  He Y, Sonnenwald T, Sprenger A, Hansen U, Fritsch A, Bruckner-Tuderman L, Schmidt G, Has C (2014).
  J Pathol. 233(3):269-80.
• Collagen VII plays a dual role in wound healing.
  Nyström A, Velati D, Mittapalli VR, Kern JS, Fritsch A, Bruckner-Tuderman L (2013).
  J Clin Invest, 123, 3498 – 3509
• Global remodeling of cellular microenvironment due to loss of collagen VII. 
  Küttner V, Mack C, Rigbolt KTG, Kern JS, Schilling O, Busch H, Bruckner-Tuderman L, Dengjel J (2013).
  Mol Syst Biol, Apr 16;9:657
• Consistency of the proteome in primary human keratinocytes with respect to gender, age, and skin localization.
  Sprenger A, Weber S, Zarei M, Engelke R, Nascimento JM, Gretzmeier C, Hilpert M, Boerries M, Has C, Busch H, Bruckner-Tuderman L, Dengjel J (2013).
  Mol Cell Proteomics. 12: 2509-21
• Integrin a3 mutations with kidney, lung and skin disease.
  Has C*, Spartà G*, Kiritsi D*, Weibel L, Moeller A, Vega-Warner V, Waters A, He Y, Anikster Y, Esser P, Straub BK, Hausser I, Bockenhauer D, Dekel B, Hildebrandt F, Bruckner-Tuderman L§, Laube GF§ (2013).
  New Engl J Med 366, 1508-1514
  (*, §, equal contribution)
• Revertant mosaicism in a human skin fragility disorder results from slippedmispairing and mitotic recombination.
  Kiritsi D, He Y, Pasmooij AMG, Onder M, Happle R, Jonkman M, Bruckner-Tuderman L, Has C (2012).
  J Clin Invest 122,1742-1746
• Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation.
  Franzke CW, Cobzaru C, Triantafyllopoulou A, Loeffek S,Horiuchi K, Threadgill DW, Kurz T, Bruckner-Tuderman L, Blobel CP (2012).
  J Ex Med 209,1105-19
• The epidermal basement membrane is a composite of separate laminin- and collagen IV-containing networks connected by aggregated perlecan, but not by nidogens.
  Behrens D, Villone D, Koch M, Brunner G, Sorokin L, Robenek H, Bruckner-Tuderman L, Bruckner P, Hansen U (2012).
  J Biol Chem, 287, 18700-9
• Lack of Plakoglobin Leads to Lethal Congenital Epidermolysis Bullosa.
  Pigors M, Kiritsi D, Krümpelmann S, Wagner N, He Y, Podda M, Kohlhase J, Hausser I, Bruckner-Tuderman L, Has C (2011).
  Hum Mol Genet 20: 1811-9
• Laminin-332 coordinates mechanotransduction and growth cone bifurcation in sensory neurons.
  Chiang LY, Poole K, Oliveira BE, Duarte N, Sierra YA, Bruckner-Tuderman L, Koch M, Hu J, Lewin GR (2011).
  Nat Neurosci 14, 993-1000
• A hypomorphic mouse model for dystrophic epidermolysis bullosa reveals disease mechanisms and responds to fibroblast therapy.
  Fritsch A, Loeckermann S, Kern JS, Braun A, Bösl MR, Bley T, Schumann H, von Elverfeldt D, Paul D, Erlacher M, Berens von Rautenfeld D, Hausser I, Fässler R, Bruckner-Tuderman L (2008).
  J Clin Invest 118, 1669-1679