Our research focuses on two main themes: detailed understanding of Wnt/β-catenin signaling via discovery of new pathway modulators and exploring the role of Wnt/β-catenin signaling in regeneration of the adult central nervous system by using zebrafish as model.
On one side, our lab is interested in understanding how Wnt/β-catenin signaling pathway activity is finetuned i.e. regulated by a variety of positive and negative modulators. Here we have two main lines of research. First, we aim at understanding the role of membrane rafts, which are the specialized cell surface nanodomains known to have critical functions in regulation of various signaling pathways, in Wnt-receptor complex activation. This is an interdisciplinary study that combines molecular and cellular biology techniques with advanced biophysical methods. Disclosure of the functional role of membrane raft nanodomains in Wnt signal transduction in a broader manner will shed light on the drug discovery studies targeting the pathway proteins preferring rafts.
Second, by exploiting the feedback regulation feature of the Wnt/β-catenin pathway, we aim to characterize novel Wnt targets that might act as pathway modifiers. To identify Wnt target genes, we will apply an RNAsequencing based whole transcriptome analysis and analyze genes that are differentially expressed upon pathway manipulation. Characterization of universally regulated Wnt targets might aid in discovery of novel Wnt pathway modifiers. Drug candidates that will be discovered via screening of small molecules targeting these modifiers will create a perfect option for targeted treatment of cancer and minimize the side effects that might emerge during treatment. Here we may exploit zebrafish embryos to identify small molecules and further validate them in adult fish.
On the other side, we aim to understand the features of Wnt-responsive cells in the highly regenerative zebrafish brain in response to injury. As zebrafish can constitutively produce new neurons throughout their life at numerous zones of stem/progenitor cells all over the brain, it represents the most widespread vertebrate neurogenesis capacity known to date and thus constitutes an ideal platform to study brain regeneration. Here we will utilize an array of molecular and cellular biology techniques including micromanipulation, histological analyses and imaging. The outcome will help us understand how brain regeneration is controlled at the molecular level and why regeneration is very limited in the mammalian brain. Furthermore, by revealing the relationship of Wnt signaling to brain regeneration, this study will pave the way for improving brain regeneration and new approaches for treatment of neurodegenerative diseases or brain injury.
Activation of Wnt/β-catenin signaling at the plasma membrane has been shown to occur via phosphorylation of the Wnt co-receptor LRP6 in raft membrane microdomains. However, the functional relevance of this finding for pathway activation and the molecular mechanisms regulating raft-specific activation had remained vague. In our previous work, we identified a new Wnt pathway modulator, Lypd6, as a positive feedback regulator of Wnt/β-catenin signaling and proved that it enhances signaling in zebrafish and Xenopus embryos and in mammalian cells (see figure). Lypd6, a GPI- anchored plasma membrane protein, partitions preferably into the raft membrane domains where it guarantees raft-specific phosphorylation of LRP6, which in turn activates the signaling. Hence, our study reveals that the activation of Wnt pathway components in specific plasma membrane microdomains is a target for cellular modifiers of the pathway. Future studies will not only elucidate the molecular mechanisms underlying such regulation but will also reveal whether these principles could be adopted for therapeutic interventions.
Ozgun Ozalp, Ozge Cark, Yagmur Azbazdar, Betul Haykir, Gokhan Cucun, Ismail Kucukaylak, Gozde Alkan-Yesilyurt, Erdinc Sezgin and Gunes Ozhan. Nradd acts as a negative feedback regulator of Wnt/ß-catenin signaling and promotes apoptosis. Biomolecules. 2021 January ; 11 (1) : 100. doi:10.3390/biom11010100.
Yagmur Azbazdar, Mustafa Karabicici, Esra Erdal and Gunes Ozhan. Regulation of Wnt signaling pathways at the plasma membrane and its misregulation in cancer. Frontiers in Cell and Developmental Biology. 2021 January .
Chai C, Cox B, Yaish D, Gross D, Rosenberg N, Amblard F, Shemuelian Z, Gefen M, Korach A, Tirosh O, Lanton T, Link H, Tam J, Permikov A, Ozhan G, Citrin J, Liao H, Tannous M, Hahn M, Axelrod J, Arretxe E, Alonso C, Martinez-Arranz I, Betés PO, Safadi R, Salhab A, Amer J, Tber Z, Mengshetti S, Giladi H, Schinazi RF, Galun E. Agonist of RORA Attenuates Non-Alcoholic Fatty Liver Progression in Mice via Upregulation of microRNA 122.. Gastroenterology. 2020 September ; S0016-5085 (20) : 34726-0. doi:10.1053/j.gastro.2020.05.056.
Demirci Y, Cucun G, Poyraz YK, Mohammed S, Heger G, Papatheodorou I, Ozhan G. Comparative Transcriptome Analysis of the Regenerating Zebrafish Telencephalon Unravels a Resource With Key Pathways During Two Early Stages and Activation of Wnt/β-Catenin Signaling at the Early Wound Healing Stage.. Frontiers in cell and developmental biology. 2020 October ; 8 : 584604. doi:10.3389/fcell.2020.584604.
Köktürk M, Altindağ F, Ozhan G, Çalimli MH, Nas MS. Textile dyes Maxilon blue 5G and Reactive blue 203 induce acute toxicity and DNA damage during embryonic development of Danio rerio.. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP. 2020 December ; 242 : 108947. doi:10.1016/j.cbpc.2020.108947.
Azbazdar Y, Ozalp O, Sezgin E, Veerapathiran S, Duncan AL, Sansom MSP, Eggeling C, Wohland T, Karaca E, Ozhan G. More Favorable Palmitic Acid Over Palmitoleic Acid Modification of Wnt3 Ensures Its Localization and Activity in Plasma Membrane Domains. Frontiers in cell and developmental biology. 2019 November ; 7 : 281. doi:10.3389/fcell.2019.00281.
Aysim Gunes, Ezgi Bagirsakci, Evin Iscan, Gulcin Cakan-Akdogan, Umut Aykutlu, Serif Senturk, Gunes Ozhan, Esra Erdal, Deniz Nart, Funda Yilmaz Barbet, Nese Atabey. Thioredoxin interacting protein promotes invasion in hepatocellular carcinoma. Oncotarget. 2018 ; 9 (96) : 36849-36866. doi:10.18632/oncotarget.26402.
Sezgin E, Azbazdar Y, Ng XW, Teh C, Simons K, Weidinger G, Wohland T, Eggeling C, Ozhan G. Binding of canonical Wnt ligands to their receptor complexes occurs in ordered plasma membrane environments. The FEBS journal. 2017 August ; 284 (15) : 2513-2526. doi:10.1111/febs.14139.
Schneider F, Waithe D, Clausen MP, Galiani S, Koller T, Ozhan G, Eggeling C, Sezgin E. Diffusion of lipids and GPI-anchored proteins in actin-free plasma membrane vesicles measured by STED-FCS. Mol Biol Cell. 2017 June ; 28 (11) : 1507-1518. doi:10.1091/mbc.E16-07-0536.
Ozhan G, Weidinger G. Wnt/β-catenin signaling in heart regeneration. Cell regeneration (London, England). 2015 July ; 4 (1) : 3. doi:10.1186/s13619-015-0017-8.
Kizil C, Küchler B, Yan JJ, Özhan G, Moro E, Argenton F, Brand M, Weidinger G, Antos CL. Simplet/Fam53b is required for Wnt signal transduction by regulating β-catenin nuclear localization. Development (Cambridge, England). 2014 September ; 141 (18) : 3529-39. doi:10.1242/dev.108415.
Wehner D, Cizelsky W, Vasudevaro MD, Ozhan G, Haase C, Kagermeier-Schenk B, Röder A, Dorsky RI, Moro E, Argenton F, Kühl M, Weidinger G. Wnt/β-catenin signaling defines organizing centers that orchestrate growth and differentiation of the regenerating zebrafish caudal fin. Cell reports. 2014 February ; 6 (3) : 467-81. doi:10.1016/j.celrep.2013.12.036.
Luz M, Spannl-Müller S, Özhan G, Kagermeier-Schenk B, Rhinn M, Weidinger G, Brand M. Dynamic association with donor cell filopodia and lipid-modification are essential features of Wnt8a during patterning of the zebrafish neuroectoderm. PloS one. 2014 January ; 9 (1) : e84922. doi:10.1371/journal.pone.0084922.
Özhan G, Sezgin E, Wehner D, Pfister AS, Kühl SJ, Kagermeier-Schenk B, Kühl M, Schwille P, Weidinger G. Lypd6 enhances Wnt/β-catenin signaling by promoting Lrp6 phosphorylation in raft plasma membrane domains. Developmental cell. 2013 August ; 26 (4) : 331-45. doi:10.1016/j.devcel.2013.07.020.
Thieme S, Gyárfás T, Richter C, Özhan G, Fu J, Alexopoulou D, Muders MH, Michalk I, Jakob C, Dahl A, Klink B, Bandola J, Bachmann M, Schröck E, Buchholz F, Stewart AF, Weidinger G, Anastassiadis K, Brenner S. The histone demethylase UTX regulates stem cell migration and hematopoiesis. Blood. 2013 March ; 121 (13) : 2462-73. doi:10.1182/blood-2012-08-452003.
Moro E, Ozhan-Kizil G, Mongera A, Beis D, Wierzbicki C, Young RM, Bournele D, Domenichini A, Valdivia LE, Lum L, Chen C, Amatruda JF, Tiso N, Weidinger G, Argenton F. In vivo Wnt signaling tracing through a transgenic biosensor fish reveals novel activity domains. Developmental biology. 2012 June ; 366 (2) : 327-40. doi:10.1016/j.ydbio.2012.03.023.
Kagermeier-Schenk B, Wehner D, Ozhan-Kizil G, Yamamoto H, Li J, Kirchner K, Hoffmann C, Stern P, Kikuchi A, Schambony A, Weidinger G. Waif1/5T4 inhibits Wnt/β-catenin signaling and activates noncanonical Wnt pathways by modifying LRP6 subcellular localization. Developmental cell. 2011 December ; 21 (6) : 1129-43. doi:10.1016/j.devcel.2011.10.015.
Ozhan-Kizil G, Havemann J, Gerberding M. Germ cells in the crustacean Parhyale hawaiensis depend on Vasa protein for their maintenance but not for their formation. Developmental biology. 2009 March ; 327 (1) : 230-9. doi:10.1016/j.ydbio.2008.10.028.
Total : 18
Restoring Tissue Homeostasis: Wnt Signaling in Tissue Regeneration After Acute Injury (2014). Wnt signalling in Development and Disease: Molecular Mechanisms and Biological Functions. Wiley-Blackwell.
Total : 1
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Yeni Wnt/Β-Katenin Sinyal İletim Yolağı DüZenleyici Elementlerinin Belirlenmesi Ve Moleküler Karakterizasyonu, Finished
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Wnt/B-Catenin Signaling In Regeneration Of Pancreas In The Adult Zebrafish, Finished
European Molecular Biology Organization - EMBO - RD : Zebrafish As A Model For Understanding Mechanisms Of Wnt/B-Catenin Signalling Viz Discovery of New Pathway Modulators In Regeneration of Adult Central Nervous System, Ongoing
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Elucidating the molecular mechanisms of Wnt-receptor complex activation in plasma membrane domains: An interdisciplinary study bridging molecular cell biology and biophysics, Finished
DEÜ BAP - Dokuz Eylul University Scientific Research Projects Coordination Unit - RD : Elucidating the molecular mechanisms of Wnt-receptor complex activation in plasma membrane domains, Finished
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Karaciğer Kanserinde Axl’in Rolü, Ongoing
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Investigation of the role of Wnt/ß-catenin signaling in brain regeneration in the adult zebrafish model, Finished
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Investigation of the role of Neurotrophin receptor associated death domain protein in regulation of Wnt/ß-catenin signaling using the zebrafish model, Ongoing
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Investigation of Wnt/β-catenin signalling at the plasma membrane in health and disease, Finished
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Development of methods and tools in iPSCs and zebrafish towards modeling of DNA sequence variants in patients with pachygyria by using genome editing technologies that will lead to personalized medicine applications, Ongoing
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : The Role of Caveolin-1 on Sorafenib Resistance in Hepatocellular Carcinoma, Ongoing
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Impact of Redox Signaling on Wnt/beta-catenin Dependant Microglial Polarization And Concomitant Neural Stem Cell Differentiation in Zebrafish And Three Dimentional Tissue Culture Models, Ongoing
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Comparative analysis of the molecular mechanisms of melanocyte regeneration and melanoma using the zebrafish model and manipulation of gene expression profiles in melanoma cells using the CRISPR/Cas9 to induce a regeneration-like progress, Ongoing
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Humanin Loaded Lipid Nanoparticles for Alzheimer’s Disease, In-Vitro and In-Vivo Evaluation, Ongoing