Mechanisms, functions and evolution of Wnt signaling pathways
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Speaker: Prof. Dr. Herbert Steinbeisser Phone: +49 6221 565050
Secretary: Phone: +49 6221 565052 |
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Overview
The FOR1036 is funded by the DFG since December 2008. In December 2011 the second funding period of the research group (Forschergruppe) started, which focuses on the analysis of the Wnt-signaling network. This regulator module is essential for embryonic development and is responsible for a number of human diseases. The signaling event triggered by Wnt-type growth factors are competitive research filed with high relevance for biological and medical research. 11 groups which work on different aspects of Wnt-signaling joined the Forschergruppe. The participating groups are affiliated with the University of Heidelberg (T. Holstein, Zoology; Centre of Organismal Studies, COS; S. Hardt, Faculty of Medicine, Cardiology; H. Steinbeisser, Faculty of Medicine, Human Genetics, M. Boutros, DKFZ and Faculty of Medicine), the Karlsruhe Institute of Technology, KIT (D. Wedlich, D. Gradl, Zoology, G. Davidson) as well as at the German Cancer Research Center, DKFZ Heidelberg and at the Institute of Molecular Biology, IMB Mainz (C. Niehrs).
The groups of A. Aulehla (EMBL, Heidelberg), M. Carl (University of Heidelberg) und S. Scholpp (KIT) were associated in the second funding period.
The Forschergruppe addresses the following questions:
- How are Wnt-proteins modified, secreted and how do they form activity gradients?
- How do components of the Wnt-signaling cascade interact inside and outside the cell?
- What are the roles of Wnt-signaling molecules in organ formation and remodeling?
The group uses a structure function approach which requires an arsenal of techniques from biochemistry, structural biology, cell biology and physiology. The members contribute a very complementary set of expertise and experimental models. In this context the animal/embryo models (Hydra/Nematostella; Drosophila, Xenopus, Zebrafish, Medaka and mouse) used by members of the Forschergruppe are of particular importance.
Relevance of the Research Area
The Wnt cascade is an evolutionarily conserved regulatory pathway essential for embryonic development in all animals. In addition, the pathway plays a crucial role in the differentiation and maintenance of tissues and organs. Perturbations in Wnt signaling impair embryonic development and can contribute to tumour formation. Two main branches of the Wnt cascade have been identified. The canonical Wnt/β-catenin pathway, which regulates differentiation and patterning processed through activation or inhibition of Wnt-specific target genes, and the non-canonical, β-catenin-independent Wnt pathway. This branch of the Wnt cascade regulates tissue polarity and morphogenetic cell movements via modulation of the cytoskeleton. Wnt signaling is initiated by secreted Wnt proteins that form morphogenic gradients and interact in recipient cells with Frizzled and ROR receptors as well as with co-receptors of the LRP family.
The regulation of Wnt proteins, their specific activities and the formation of Wnt activity gradients are subjects of intense research. A prime example of the dynamic regulation of Wnt signaling is the oscillating Wnt activity in developing somites. Precise spatial regulation of Wnt activity is also required in the anterior/posterior patterning and the establishment of left/right asymmetry in the developing vertebrate brain. Wnt proteins can be controlled spatially and temporally on the level of gene transcription, however the cis-regulatory elements of the Wnt genes are only poorly characterised. Since Wnts are secreted proteins the export out of the cell offers an additional level of control. The regulation of Wnt protein secretion and the components involved, such as Evi/Wntless, has recently become a focus of more intense research. Wnt proteins that localise extra cellularly are also tightly regulated. Secreted factors such as the Dkk and sFRP proteins can inhibit Wnt signaling by interacting with the Wnt-ligand, the receptors and the co-receptors. The sFRPs exhibit a biphasic activity that can both augment and inhibit Wnt signaling dependent on the cellular context. The mechanisms that underlie many of these activities are still poorly understood. In addition, very little is known about the stability of the Wnt proteins in the extracellular environment. Controlled stabilisation or degradation of Wnt proteins may indeed represent a novel layer of regulation.
The Frizzled/LRP receptor complex transmits the Wnt signal into the cell. This cascade requires the association of Dsh with Frizzled and the phosphorylation of the cytoplasmic domain of LRP. So far only a few kinases that act on the LRP/Frizzled complex, such as GSK3 and CK1, have been characterised. The identification of additional kinases that modulate Wnt signaling intracellularly will be of great importance in the future. When the Wnt/β-catenin signal reaches the nucleus, TCF/Lef transcription factors regulate the transcription of target genes. TCFs act in a context-dependent manner, but it is not understood how this is achieved. The functional characterisation of TCF splice variants and co-factors is important for the understanding of this regulatory layer of the Wnt cascade. Non canonical Wnt signaling is not dependent on β-catenin and TCF function, but involves the activity of small GTPases such as Rho and Rac as well as PKC and JNK. Nevertheless, the means by which non-canonical Wnt signaling is converted into the modulation of the cytoskeleton, which is the basis for changes in cell polarity and behaviour, have not yet been fully elucidated. Recent data indicate that the asymmetric distribution of Wnt pathway component within a cell is crucial for the establishment of cell and tissue polarity.
