Wnt/β-catenin signaling, a vital signal transduction cascade known over the last three decades, takes its name from a family of secreted glycoproteins, the Wnt proteins, which act as pathway ligands and from the downstream effector molecule, β-catenin. Owing to its vital roles in the regulation of embryonic development, maintenance of adult tissue homeostasis and regeneration of various animal tissues and organs (see figure); misregulation of the pathway causes various cancers, genetic disorders, and degenerative diseases. A tight regulation that involves a large number of positive and negative modifiers of the pathway is thus necessary to avoid the detrimental outcomes of pathway misregulation. Understanding the molecular mechanisms of this regulation will help to elucidate its association to human diseases and to develop new potential therapeutic targets.RESEARCH INTERESTS
Our research focuses on two main themes: detailed understanding of Wnt/β-catenin signaling via the 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 a model.
On one side, our lab is interested in understanding how Wnt/β-catenin signaling pathway activity is fine tuned 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 the 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 RNA sequencing based whole transcriptome analysis and analyze genes that are differentially expressed upon pathway manipulation. Characterization of universally regulated Wnt targets might aid in the 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 the 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.