Molekulare Dermatologie und Stammzellen-Forschung

Prof. Eliane J. Müller
Prof. Dr. Eliane J. Müller (Group Leader)

Investigations in the Molecular Dermatology and Stem Cell Research group focus on elucidating the signals governing epidermal renewal from stem cells to differentiated keratinocytes, and how these signals malfunction in specific skin diseases. This research is of a translational nature, and has the ultimate goal to develop novel and specific therapeutic applications based on an improved understanding of the detailed mechanisms the skin uses to renew itself.

Stem cell-driven epidermal renewal
The epidermis is the outermost layer of the skin, and is composed mainly of keratinocytes that assemble into a stratified squamous epithelium. Like epidermal appendages such as hair follicles, sebaceous and sweat glands, the epidermis is renewed throughout the entire life span of an organism. Epidermal renewal begins when a keratinocyte progenitor leaves the stem cell compartment, undergoes a limited number of mitotic divisions, exits the cell cycle and commits to terminal differentiation. At the end of this phase the post-mitotic cells detach from the basement membrane to build up the overlaying stratified epithelium. Although highly coordinated, this sequence of events is endowed with a remarkable versatility, which enables the quiescent keratinocytes in the stem cell and early postmitotic compartment to re-integrate into the cell cycle and become migratory when necessary, for example after wounding. It is this versatility that represents the Achilles heel of epithelial cells, as disruption of these complex mechanisms leads to severe skin diseases such as cancer, psoriasis and also the autoimmune disease Pemphigus vulgaris.

Pemphigus vulgaris
In the laboratory, the main emphasis of recent years was on defining the molecular mechanisms leading to the severe blistering disease Pemphigus vulgaris. In the majority of the patients the etiology of this disease relies on autoantibodies directed against the adhesion molecule desmoglein (Dsg) 3. Dsg3 is part of the desmosome, a multiprotein complex which confers strong intercellular adhesiveness in particular in the germinative layer of the epidermis and skin appendages that contain stem cells and proliferative keratinocytes. Our laboratory has contributed to a novel understanding of the pathophysiology of Pemphigus vulgaris that relies on antibody triggered deregulation of signaling cascades required for the coordinated and controlled renewal of the epidermal sheet. This allows us for the first time to study the molecular mechanisms of stem cell activation including epigenetic changes in human skin by using Pemphigus vulgaris patients as a model system. One of the molecules found to be centrally involved in this process is the armadillo protein plakoglobin through both, structural and signaling activities.

Plakoglobin: an orphan rescued
Although the lack of a developmental phenotype in plakoglobin knock-out mice seemed to exclude a signaling role of plakoglobin, the results from various laboratories including ours today confirms an important signaling role of plakoglobin in epidermal renewal.
Our ongoing studies support that plakoglobin is a central transcriptional effector in the Wnt signaling pathway, which is of importance during development, tissue regeneration and in particular in stem cell regulation. By performing a genome-wide promoter screen we challenge the current understanding of Wnt signaling; it revealed that plakoglobin targeted promoters significantly overlap with those of the classical effector in the Wnt pathway, ß-catenin. This points towards the possibility that the function of these two armadillo proteins is interdependent and the knock-out phenotype of one molecule alone cannot reveal its entire function.

Future directions
The exact role of plakoglobin in the stem cell compartment and epithelial tissue homeostasis is currently not understood. It is our aim to address this question in normal tissue renewal as well as in hyperproliferative diseases including cancer.

Publikationen - letzte 5 Jahre

A. Galichet, L. Borradori, E.J. Müller. A new light on an old disease: Adhesion signaling in pemphigus vulgaris. J. Invest. Dermatol, 134, 8-10, 2014 (Comment on MAPKAP kinase 2 (MK2)-dependent and -independent models of blister formation in pemphigus vulgaris. [J Invest Dermatol. 2014])

M. Drögemüller, V. Jagannathan, D. Becker, C. Drögemüller, C. Schelling, J. Plassais, C. Kaerle, C. Dufaure de Citres, A. Thomas, E. J. Müller, M. M. Welle, P. Roosje, T. Leeb. A Mutation in the FAM83G Gene in Dogs with Hereditary Footpad Hyperkeratosis (HFH). PLoS Genet., in press

Sayar S.S., Rüegg S., Schmidt E., Sibilia M., Siffert M., Suter M.M., Galichet A., Müller E. J.. EGFR inhibitors Erlotinib and Lapatinib ameliorate epidermal blistering in Pemphigus vulgaris in a non-linear, V-shaped relationship, Experimental Dermatology, 23, 33-8, 2014; PMID: 24279293

Jagannathan V, Bannoehr J, Plattet P, Hauswirth R, Drögemüller C, Drögemüller M, Wiener DJ, Doherr M, Owczarek-Lipska M, Galichet A, Welle MM, Tengvall K, Bergvall K, Lohi H, Rüfenacht S, Linek M, Paradis M, Müller EJ, Roosje P, Leeb T., A Mutation in the SUV39H2 Gene in Labrador Retrievers with Hereditary Nasal Parakeratosis (HNPK) Provides Insights into the Epigenetics of Keratinocyte Differentiation. PLoS Genet. 2013 Oct;9(10):e1003848. doi: 10.1371/journal.pgen.1003848. Epub 2013 Oct 3; PMID: 24098150

Tokonzaba E., Chen J., Cheng X., Den, Z., Ganeshan R., Műller E.J. and Koch P.J.. Plakoglobin as a Regulator of Desmocollin Gene Expression. J. Investigative Dermatology (2013) epub; PMID: 23652796

Luff J.A. , Yuan H., Suter M.M., Müller E.J., Schlegel R., Moore P.F.. Canine keratinocytes upregulate type I interferons and proinflammatory cytokines in response to poly(dA:dT) but not to canine papillomavirus. Vet. Immunol. Immunopathol. 153, 177-186, (2013); PMID: 23557936

Wiener D.J., Gurtner C., Panakova L., Mausberg T., Roosje P., Müller E.J., Drögemüller C., Leeb T, Welle M.M., Clinical and histological characterization of hair coat and glandular tissue of Chinese crested Dogs, Vet Dermatol. (2013) epub, 274-e62; PMID: 23413772

Klukowska-Rötzler J., Chervet L., Müller E.J., Roosje P., Marti E., Janda J., Expression of thymic stromal lymphopoietin in canine atopic dermatitis, Vet. Dermatol. 24, 54-59, (2013); PMID: 23331680

Swope D., Li J., Muller E.J., and Radice G.L. Analysis of a Jup Hypomorphic Allele Reveals a Critical Threshold for Postnatal Viability, Genesis, 50, 717-27, (2012); PMID: 22522917

Schulze K., Galichet A., Sayar B.S., Scothern A., Howald D., Zymann H., Zenhaeusern D., Siffert M., Bolli R., Koch P.J., Garrod D., Suter M.M., Müller E.J.. An adult passive transfer mouse model to study desmoglein 3 signaling in pemphigus vulgaris. J Invest Dermatol., 132, 346-355 (2012); PMID: 21956125

Bongiovanni L., Müller E.J., and Della Salda L. Survivin in skin pathologies. Exp. Dermatology, 20, 457-463 (2011); PMID: 21585553

Li J., Swope D., Raess N., Cheng L., Muller E. J. and Radice G. L.. Cardiac-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of ß-catenin signaling, Mol Cell Biol, 31,1134-1144 (2011); PMID: 21245375

Mahoney M.G., Müller E.J., and Koch P.J.. Desmosomes and Desmosomal Cadherin Function in Skin and Heart Diseases—Advancements in Basic and Clinical Research. Dermatology Research and Practice. Volume 2010, Article ID 725647, 1-3, 2010, editorial; PMID: 20885972

Chervet L., Galichet A., McLean I.W.H, Chen H., Suter M., Roosje P.J.§; and Müller E.J.§;. Missing C-terminal filaggrin expression, NFkappaB activation and hyperproliferation identify the dog as a putative model to study epidermal dysfunction in atopic dermatitis. Exp. Dermatol., 19, e343-6 (2010); PMID: 20626465
§ equal contribution

Haerdi-Landerer C., Steiner A., Suter M.M. Primary bovine synoviocyte culture - a useful tool for in vitro drug testing? Vet. Journal, 188:58-63 (2010); PMID: 20347355

Haerdi-Landerer M. C. Habermacher J., Wenger B., Suter M. M., Steiner A. Slow release antibiotics for treatment of septic arthritis in large animals. Veterinary Journal 184, 14-20, (2010); PMID: 19345594

Getsios§; S., Jens Waschke§; J., Borradori§; L., Michael Hertl§; M. and Eliane J. Müller. Meeting report: From cell signalling to novel therapeutic concepts – International Pemphigus Meeting on advances in pemphigus research and therapy. J. Invest. Dermatol, 130, 1764-8 (2010); PMID: 20548314
§ equal contribution

Caldelari R. and Müller E.J. Short and long-term cultivation of embryonic and neonatal murine keratinocytes (Book Chapter), Methods Mol Biol., 633, 125-38 (2010); PMID: 20204625

Rüfenacht S., Straub R., Steinmann B., Winand N., Bidaut A., Stoffel M.H., Gerber V., Wyder M., Müller E., Roosje P.J. [Swiss warmblood horse with symptoms of hereditary equine regional dermal asthenia without mutation in the cyclophylin B gene (PPIB)]. Schweiz Arch Tierheilkd. Apr;152(4):188-92 (2010); PMID: 20361398

Acehan D., Petzold C., Gumper I., Sabatini D.D., Müller E.J., Cowin P., Stokes D.L. Plakoglobin is required for effective intermediate filament anchorage to desmosomes. J. Invest Dermatol., 128, 2665-2675, (2008); PMID: 18496566

Huguenin M., Müller E.J., Trachsel-Rösmann S., Oneda B., Ambort D., Sterchi E.E., Lottaz D. The Metalloprotease Meprin b Processes E-Cadherin and Weakens Intercellular Adhesion. PLoS, 3(5), e2153 (2008); PMID: 18478055

Haerdi-Landerer, MC, Suter, M.M., Steiner, A., Wittenbrink MM., Pickl A., Gander BA. In vitro cell compatibility and antibacterial activity of microencapsulated doxycycline designed improved localized therapy of septic arthritis. J Antimicrob Chemother 61, 332-340 (2008).

Keller S.M., Schade B., Rickenbacher A., Brugnera E., Müller E.J., Suter M.M., Guscetti F. A comprehensive test system to select heterologous antibodies specific for immunohistochemistry on canine tissues as exemplified for antibodies to p53.  J. Comp. Pathol. 137, 59-70 (2007); PMID: 17629968

Dusek L.R., Godsel L.M., Chen F., Strohecker A., Getsios S., Harmon R., Müller E.J., Caldelari R., Cryns V.L. Green K.J. Plakoglobin deficiency protects keratinocytes from apoptosis. J. Invest Dermatology, 127, 792-801 (2007); PMID: 17110936

Müller E.J., Hunziker T., Suter M.M. Keratin intermediate filament retraction is linked to plakoglobin-dependent signaling in Pemphigus vulgaris. Response to [J. Am. Acad Dermatol 2006; 54:513-6]. J. Am. Acad. Dermatol.,56, 890-891 (2007); PMID: 17437895

Williamson L., Suter M.M., Olivry T., Wyder M., Müller E.J. Upregulation of c-Myc may contribute to Pathogenesis in Canine Pemphigus Vulgaris. Vet. Dermatol., 18, 12-17 (2007); PMID: 17222234

Haerdi-Landerer M.C., Suter, M.M., Steiner A. Intra-articular application of Doxycycline in calves. Am J Vet Res 68, 1324-31 (2007)

Mahoney M.G., Müller E.J., Viewpoint in "Controversies in Experimental Dermatology by Amagai M., Ahmed A.R., Kitajima Y., Bystryn J.C., Milner Y., Gniadecki R., Hertl M., Pincelli C., Fridkis-Hareli M., Aoyama Y., Frusic-Zlotkin M., Müller E.J., David M., Mimouni D., Vind-Kezunovic D., Michel B., Mahoney M., Grando S. Are desmoglein autoantibodies essential for the immunopathogenesis of pemphigus vulgaris, or just "witnesses of disease"? in "Controversies in Experimental Dermatology”. J. Exp. Dermatology, 15, 815-831 (2006); PMID: 16984264

Olivry T., Lavoy A., Dunston S.M., Brown R.S., Lennon E.M., Warren S.J., Prisayanh P., Müller E.J., Suter M.M., Dean G.A. Desmoglein-1 is a Minor Autoantigen in Dogs with Pemphigus Foliaceus. Vet. Immunol., 110, 245-255 (2006); PMID: 16293316

Weitere ausgewählte Publikationen

Suter M.M., Schulze K., Welle M., Roosje P., Mueller E.J. The Keratinocyte in Epidermal Renewal and Defence. Review, Vet. Dermatol. Volume 20, 515-532 (2009); PMID: 20178490

Müller E.J., L. Williamson L., Kolly C., Suter M.M. Outside-in signaling through integrins and cadherins: a central mechanism to control epidermal growth and differentiation? Invited review in “Perspectives: Signaling through cell junctions”, J. Invest. Dermatol, 128,501-516 (2008); PMID: 18268536

Williamson L., Hunziker T., Suter M.M., Müller E.J. Nuclear c-Myc: a molecular marker for early stage Dsg3-antibody mediated pemphigus vulgaris. J. Invest. Dermatol.,  127, 1549-1555 (2007); PMID: 17315040

De Bruin A., Caldelari R., Williamson L., Suter M.M., Hunziker T., Wyder M., Müller E.J. Plakoglobin-dependent disruption of the desmosomal plaque in Pemphigus vulgaris. Exp. Dermatol., 16, 468-475 (2007); PMID: 17518986

Kolly C., Zakher A., Strauss C., Suter M.M., Müller E.J. Keratinocyte Transcriptional Regulation of the human c-Myc promoter occurs via a novel Lef/Tcf binding element distinct from neoplastic cells. FEBSLetters, 580, 1969-1976 (2007); PMID: 17466981

Williamson L., Raess N.A., Caldelari R., Zakher A., de Bruin A., Posthaus H., Bolli R., Hunziger T., Suter M.M., Müller E.J. Pemphigus vulgaris identifies Plakoglobin as key suppressor of C-MYC in the skin. EMBO J., 25,3298-3309 (2006); PMID: 16871158

Müller E.J., Caldelari R., Kolly C., Williamson L., Baumann D., Richard G., Jensen P., Girling P., Delprincipe F., Wyder M., Balmer V., Suter M.M. Consequences of depleted SERCA2-gated calcium stores in the skin. J. Invest. Dermatol., 126, 721-731 (2006) [featured articel; commentary by Carolyn R Byrne, J. Invest Dermatol 126, 702-703 (2006)]; PMID: 16397524

Yin T., Getsios S., Caldelari R., Kowalczyk A.P., Müller E.J., Green K.J. Mechanisms of Plakoglobin-Dependent Adhesion: Desmosome Specific Functions in Assembly and Regulation by EGFR. J. Biol. Chem., 280, 40355-40363 (2005); PMID: 16183992

Yin T., Getsios S., Caldelari R., Kowalczyk A.P., Müller E.J., Jones J.C.R. , Green K. J. Plakoglobin Suppresses Keratinocyte Motility Through Both Cell-Cell Adhesion-dependent and -independent Mechanisms. Proc. Natl. Acad. Sci. USA. 102, 5420-5425 (2005); PMID: 15805189

Kolly K. , Suter M. , Müller E.J. Proliferation, cell cycle exit and onset of terminal differentiation in cultured keratinocytes: Pre-programmed pathways in control of c-Myc and Notch1 prevail over extracellular calcium signals. J. Invest. Dermatol. 124, 1014-1025 (2005) [+cover]; PMID: 15854044

Pronovost M., Suter M.M., Mueller E.J., Sirios J., Doré M. Expression and regulation of cyclooxygenase-2 in normal and neoplastic canine keratinocytes. Vet. Comp. Oncol. 2, 222-233 (2004).

Müller E.J., Caldelari R., Posthaus H. Role of substilisin-like convertase in cadherin processing or the conundrum to stall cadherin function by covertase inhibitors in cancer therapy (review). Journal of Molecular Histology.
Vol. 35, 263-275 (2004); PMID: 15339046

Bidaut A.P., Gross T.L., Noli C., Welle M., Suter M.M. Acrochordonous plaques in two Bulldogs and a Pug dog. Vet. Dermatol. 14(3), 177-179 (2003); PMID: 12791052

Posthaus H., Dubois C. M., Müller E.J. Novel insights into cadherin processing by subtilisin-like convertases. FEBS letters 536, 203-208 (2003); PMID: 12586364

Müller E.J., Kernland K., Caldelari R., Wyder M., Balmer V., Hunziker T. Unusual Pemphigus Phenotypein presence
of a Dsg1 and Dsg3 Autoantibody Profile. J. Invest. Dermat. 118, 551-555 (2002). §equal contribution; PMID: 11874500

Posthaus H., Williamson L., Baumann D., Kemler R., Caldelari R., Suter M.M., Schwarz H., Müller E.J. b-Catenin is not required for proliferation and differentiation of epidermal mouse keratinocytes.  J. Cell Sci. 105: 4587-4595 (2002); PMID: 12415003

Vonlaufen N., Müller N., Keller N., Naguleswaran A., Bohne W., McAllister M.M. Björkman C., Müller E.J., Caldelari R., Hemphill A. Exogenous NO triggers Neospora caninum tachyzoite-to-bradyzoite stage conversion in murine epidermal keratinocyte cell cultures. Int. J. of Parasitol. 32, 1253-1265 (2002); PMID: 12204225

Caldelari R., de Bruin A., Baumann D., Suter M.M., Bierkamp C., Balmer V.,  Müller E.J. A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris. J. Cell Biol.153, 823-834 (2001). §equal contribution; PMID: 11352942

Caldelari R., Suter M.M., Baumann D., de Bruin A., Müller E.J.  Long-Term Culture of  Murine Epidermal  Keratinocytes. J. Invest. Dermatol. 114, 1064-1065 (2000) [+cover]; PMID: 10792572

Müller E.J., Caldelari R., Levine R., Kaplan S., Baron A., Rohrbach B., Wyder M., Balmer V. and  Suter  M.M.
Cloning of Canine DSG1 and Evidence for Alternative  Polyadenylation. J. Invest. Dermat. 114, 1064-1065 (2000); PMID: 10844571