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.
M. Kokturk, S. Yıldırım, M. H. Calimli, M. S. Nas, F. Ibaokurgil, G. Ozhan, M. Atamanalp & G. Alak. Perspective on green synthesis of RP-Pd/AC NPs: characterization, embryonic and neuronal toxicity assessment. International Journal of Environmental Science and Technology. 2023 January . doi:10.1007/s13762-022-04005-1. Download
Azbazdar Y, Poyraz YK, Ozalp O, Nazli D, Ipekgil D, Cucun G, Ozhan G. High-fat diet feeding triggers a regenerative response in the adult zebrafish brain.. Molecular neurobiology. 2023 January ; 60 (2) : 1-21. doi:10.1007/s12035-023-03210-4. Download
D. Engur, I. Ercan, C. Kiser, K.U. Tufekci, S. Soy, S.C. Micili, G. Ozhan, S. Guven, A. Kumral, S. Genc. Hydrogen peroxide signaling modulates neuronal differentiation via microglial polarization and Wnt/β-catenin pathway. European Review for Medical and Pharmacological Sciences.. 2023 June ; 27 (11) : 5083-5096. doi:10.26355/eurrev_202306_32625. Download
Kokturk M, Yıldırım S, Atamanalp M, Kiliclioglu M, Ucar A, Ozhan G and Alak G.. Mitigation potential of zingerone and rutin on toxicity mechanisms of nickel to zebrafish based on morphological, DNA damage and apoptosis outcome analysis. Journal of Trace Elements in Medicine and Biology. 2023 December ; 80 : 127268. doi:10.1016/j.jtemb.2023.127268. Download
Atalar MN, Kokturk M, Altindag F, Ozhan G, Ozen T, Demirtas I, Gulcin I. LC-ESI-MS/MS analysis of secondary metabolites of different St. John's wort (Hypericum perforatum) extracts used as food supplements and evaluation of developmental toxicity on zebrafish (Danio rerio) embryos and larvae. South African Journal of Botany. 2023 August ; 159 : 580-587. doi:10.1016/j.sajb.2023.06.031. Download
Azbazdar Y, Demirci Y, Heger G, Ipekgil D, Karabicici M, Ozhan G. Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β-catenin signaling and tumor growth.. Molecular oncology. 2023 September . doi:10.1002/1878-0261.13520. Download
Demirci Y, Heger G, Katkat E, Papatheodorou I, Brazma A, Ozhan G. Brain Regeneration Resembles Brain Cancer at Its Early Wound Healing Stage and Diverges From Cancer Later at Its Proliferation and Differentiation Stages.. Frontiers in cell and developmental biology. 2022 February ; 10 : 813314. doi:10.3389/fcell.2022.813314. Download
Hesaraki M, Bora U, Pahlavan S, Salehi N, Mousavi SA, Barekat M, Rasouli SJ, Baharvand H, Ozhan G, Totonchi M. A Novel Missense Variant in Actin Binding Domain of MYH7 Is Associated With Left Ventricular Noncompaction.. Frontiers in cardiovascular medicine. 2022 April ; 9 : 839862. doi:10.3389/fcvm.2022.839862. Download
Kokturk M, Yıldırım S, Yigit A, Ozhan G, Bolat I, Alma, MH, Menges N, Atamanalp M and Alak G.. What is the eco-toxicological level and effects of Graphene oxide-Boramidic Acid (GO-ED-BA NP)? : In vivo study on Zebrafish embryo/larvae.. Journal of Environmental Chemical Engineering. 2022 October ; 10 (5) : 108443. doi:10.1016/j.jece.2022.108443. Download
Kokturk M, Yıldırım S, Atamanalp M, Calimli MH, Nas MS, Bolat I, Ozhan G, and Alak G. Assessment of oxidative DNA damage, apoptosis and histopathological alterations on zebrafish exposed with green silver nanoparticle. Chemistry and Ecology. 2022 August ; 38 (7) : 655-60. doi:10.1080/02757540.2022.2108808. Download
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. 2021 April ; 242 : 108947. doi:10.1016/j.cbpc.2020.108947. Download
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. Download
Evin Iscan, Umut Ekin, Gokhan Yildiz, Ozden Oz, Umur Keles, Aslı Suner, Gulcin Cakan-Akdogan, Gunes Ozhan, Marta Nekulova, Borivoj Vojtesek, Hamdiye Uzuner, Gökhan Karakülah, Hani Alotaibi and Mehmet Ozturk. TAp73β Can Promote Hepatocellular Carcinoma Dedifferentiation. Cancers. 2021 February ; 13 (4) : 783. doi:10.3390/cancers13040783. Download
Azbazdar Y, Karabicici M, Erdal E, Ozhan G. Regulation of Wnt Signaling Pathways at the Plasma Membrane and Their Misregulation in Cancer.. Frontiers in cell and developmental biology. 2021 January ; 9 : 631623. doi:10.3389/fcell.2021.631623. Download
Akbari S, Kunter İ, Azbazdar Y, Ozhan G, Atabey N, Karagonlar ZF, Erdal E. LGR5/R-Spo1/Wnt3a axis promotes stemness and aggressive phenotype in hepatoblast-like hepatocellular carcinoma cell lines.. Cellular signalling. 2021 June : 109972. doi:10.1016/j.cellsig.2021.109972. Download
Dhasmana D, Veerapathiran S, Azbazdar Y, Nelanuthala AVS, Teh C, Ozhan G, Wohland T. Wnt3 Is Lipidated at Conserved Cysteine and Serine Residues in Zebrafish Neural Tissue.. Frontiers in cell and developmental biology. 2021 May ; 9 : 671218. doi:10.3389/fcell.2021.671218. Download
Kokturk M, Yıldırım S, Nas MS, Ozhan G, Atamanalp M, Bolat I, Calimli MH, Alak G. Investigation of the Oxidative Stress Response of a Green Synthesis Nanoparticle (RP-Ag/ACNPs) in Zebrafish.. Biological trace element research. 2021 August . doi:10.1007/s12011-021-02855-3. Download
Karabicici M, Azbazdar Y, Ozhan G, Senturk S, Firtina Karagonlar Z, Erdal E. Changes in Wnt and TGF-β Signaling Mediate the Development of Regorafenib Resistance in Hepatocellular Carcinoma Cell Line HuH7.. Frontiers in cell and developmental biology. 2021 August ; 9 : 639779. doi:10.3389/fcell.2021.639779. Download
Ozhan, G. Editorial: Wnt Signaling at the Plasma Membrane: Activation, Regulation and Disease Connection. Frontiers in Cell and Developmental Biology. 2021 October ; 9 : 2994. doi:10.3389/fcell.2021.780163. Download
Karabicici M, Azbazdar Y, Iscan E, Ozhan G. Misregulation of Wnt Signaling Pathways at the Plasma Membrane in Brain and Metabolic Diseases.. Membranes. 2021 October ; 11 (11) : 844. doi:10.3390/membranes11110844. Download
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 ; 159 (3) : 999-1014.e9. doi:10.1053/j.gastro.2020.05.056. Download
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. Download
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. Download
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. Download
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. Download
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. Download
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. Download
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. Download
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. Download
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. Download
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. Download
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. Download
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. Download
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. Download
Total : 35
Zebra Balığı Nörodejeneratif Hastalık Modelleri (2023). Zebra Balığının Model Organizma Olarak Kullanımı. Türkiye Klinikleri.
Hücre Ölümü Çalışmalarında Zebrabalığı Modelinin Kullanımı (2022). Hastalıkta ve Sağlıkta Hücre Ölümü: Mekanizmaları ve Deneysel Araştırma Modelleri. Hücre Ölümü Araştırma Derneği.
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 : 3
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, Finished
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, Finished
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, Finished
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : The Role of Caveolin-1 on Sorafenib Resistance in Hepatocellular Carcinoma, Finished
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, Finished
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, Finished
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Investigation of invasion, motility and proliferation capacities of leukemic cells with high plasticity in the zebrafish (Dario rerio) model, Ongoing
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Investigation of the roles of Wnt/β-catenin signaling and p75NTR homolog Nradd in development of neuronal degeneration and regeneration responses in Alzheimer's disease in a zebrafish model of amyloid-β42 toxicity, Ongoing
DEÜ BAP - Dokuz Eylul University Scientific Research Projects Coordination Unit - RD : The effects of Humanin and Donepezil on brain neurotransmitter levels in the treatment of Alzheimer's disease: a comparative study of the molecular and behavioral level in a zebrafish model of amyloid-beta toxicity, Finished
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Investigation of the Role of Carboxyesterase Notum in Regenerative Neurogenesis in Zebrafish (Dario Rerio) Brain Model, Ongoing
The Scientific and Technological Research Council of Turkey - TUBITAK - RD : Discovering the genetic causes of idiopathic infertility due to meiotic arrest and elucidating the functional roles of the mutated genes, Ongoing
Other National Funding Body - RD : Establishment of a Zebrafish Xenograft Model for Personalized Treatment of Leukemias, Funded, Not Started
Health Institutes of Turkey- TUSEB - RD : Comparison of the molecular mechanisms of brain cancer and brain regeneration using the zebrafish model and convergence of glioblastoma cells to regenerating cells using CRISPR/Cas9 genome editing, Funded, Not Started
Other National Funding Body - RD : In vitro and in vivo investigation of mRNA transport potentials of novel cationic polymers, Ongoing