Özhan Lab. on Development and Regeneration

OVERVIEW

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.

RESEARCH INTERESTS

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.

RESEARCH HIGHLIGHTS

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.

Group Members

Özhan Lab. on Development and Regeneration

Group Leader

Gunes OZHAN BAYKAN
gunes.ozhan@ibg.edu.tr
+90 232 299 41 00 (5061)
+9 02322994156

Ebru Turhanlar Research Technician ebru.turhanlar@ibg.edu.tr

Yağmur Azbazdar PhD Student yagmur.azbazdar@msfr.ibg.edu.tr

Yeliz Demirci Garanlı PhD Student yeliz.demirci@msfr.ibg.edu.tr

Esra Katkat PhD Student esra.katkat@ibg.edu.tr

Özgün Özalp PhD Student ozgun.ozalp@msfr.ibg.edu.tr

Gökhan Cucun MSc Student gokhan.cucun@msfr.ibg.edu.tr

Özge Çark MSc Student ozge.cark@msfr.ibg.edu.tr

Selected Publications

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 Aug ; 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 Jun ; 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 Jul ; 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 Sep ; 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 Feb ; 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 Jan ; 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 Aug ; 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 Mar ; 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 Jun ; 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 Dec ; 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 Mar ; 327 (1): 230-9. doi:10.1016/j.ydbio.2008.10.028.

Selected Book Chapters

Günes Özhan and Gilbert Weidinger (2014). Wnt signalling in Development and Disease: Molecular Mechanisms and Biological Functions 'Restoring Tissue Homeostasis: Wnt Signaling in Tissue Regeneration After Acute Injury'. Wiley-Blackwell.

Projects

Tubitak - RD : WNT/Β-KATENİN SİNYAL İLETİMİNİN BEYİN REJENERASYONUNDAKİ ROLÜNÜN ERİŞKİN ZEBRA BALIĞI MODELİNDE ARAŞTIRILMASI , 2016-06-01/2019-06-01

BRITISH COUNCIL / TÜBİTAK ORTAK - RD : SAĞLIKTA VE HASTALIKTA PLAZMA MEMBRANINDA WNT/ß-KATENİN SİNYAL İLETİMİNİN ARAŞTIRILMASI , 2018-06-15/2020-06-15

Tubitak - RD : WNT-RESEPTÖR KOMPLEKSİNİN HÜCRE MEMBRANI ALANLARINDAKİ AKTİVASYONUNUN MOLEKÜLER MEKANİZMALARININ ANLAŞILMASI: MOLEKÜLER HÜCRE BİYOLOJİSİ VE BİYOFİZİK ALANLARINDA DİSİPLİNLERARASI BİR ÇALIŞMA , 2014-10-01/2017-10-01

Tubitak - RD : WNT/B-CATENİN SIGNALING IN REGENERATION OF PANCREAS IN THE ADULT ZEBRAFISH , 2015-11-25/2017-11-24

DEU BAP - RD : WNT-RESEPTÖR KOMPLEKSİNİN HÜCRE MEMBRANI ALANLARINDAKİ AKTİVASYONUNUN MOLEKÜLER MEKANIZMALARININ ANLAŞILMASI , 2014-08-15/2017-08-15

EMBO - RD : ZEBRAFISH AS A MODEL FOR UNDERSTANDING MECHANISMS OF WNT/B-CATENIN SIGNALLING (1) VIA DISCOVERY OF NEW PATHWAY MODULATORS AND (2) IN REGENERATION OF ADULT CENTRAL NERVOUS SYSTEM , 2015-01-01/2019-12-31

Awards

  • Güneş ÖZHAN - Incentive Award by METU Prof. Mustafa N. Parlar Education and Research Foundation, 2018

Contact

Özhan Lab. on Development and Regeneration

Group Leader

Gunes OZHAN BAYKAN
gunes.ozhan@ibg.edu.tr
+90 232 299 41 00 (5061)
+9 02322994156