Cleavage of the Wnt Receptor Ryk Regulates Neuronal Differentiation during Cortical Neurogenesis
ABSTRACT Ryk is a transmembrane receptor tyrosine kinase (RTK). It functions as a receptor of Wnt proteins required for cell-fate determination, axon guidance, and neurite outgrowth in different organisms; however, the molecular mechanism of Ryk signaling is unknown. Here, we show that Ryk is cleaved, permitting the intracellular C-terminal fragment of Ryk to translocate to the nucleus in response to Wnt3 stimulation. We also show that the cleaved intracellular domain of Ryk is required for Wnt3-induced neuronal differentiation in vitro and in vivo. These results demonstrate an unexpected mechanism of signal transduction for Ryk as a Wnt receptor, in which the intracellular domain itself functions as the transducing molecule to bring extracellular signals from the cell surface into the nucleus, to regulate neural progenitor cell differentiation.
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ABSTRACT: In all multicellular animals, successful embryogenesis is dependent on the ability of cells to detect the status of the local environment and respond appropriately. The nature of the extracellular environment is communicated to the intracellular compartment by ligand/receptor interactions at the cell surface. The Wnt canonical and non-canonical signalling pathways are found in the most primitive metazoans, and they play an essential role in the most fundamental developmental processes in all multicellular organisms. Vertebrates have expanded the number of Wnts and Frizzled receptors and have additionally evolved novel Wnt receptor families (Ryk, Ror). The multiplicity of potential interactions between Wnts, their receptors and downstream effectors has exponentially increased the complexity of the signal transduction network. Signalling through each of the Wnt pathways, as well as crosstalk between them, plays a critical role in the establishment of the complex architecture of the vertebrate central nervous system. In this review, we explore the signalling networks triggered by non-canonical Wnt/receptor interactions, focussing on the emerging roles of the non-conventional Wnt receptors Ryk and Ror. We describe the role of these pathways in neural tube formation and axon guidance where Wnt signalling controls tissue polarity, coordinated cell migration and axon guidance via remodelling of the cytoskeleton.Neurosignals 03/2012; 20(3):202-20. DOI:10.1159/000332153 · 4.03 Impact Factor
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ABSTRACT: Synaptic plasticity, in its broadest sense, can be defined as the ability of synapses to be modified structurally and functionally in response to various internal and external factors. Growing evidence has established that at the very core of these modifications are alterations in the cytoskeletal architecture. This discovery has led to the unearthing of a number of signaling pathways that might be involved in cytoskeletal regulation and also in the regulation of other aspects of synapse development and plasticity. In this regard, polarity proteins and secreted morphogens such as the Wnt proteins, typically involved in embryonic development, are emerging as critical determinants of synaptic growth and plasticity. However, their mechanism of action at synapses needs further investigation. Additionally, not much is known about how these morphogens are secreted or transported across synapses. Using the Drosophila larval NMJ as a model system, I have addressed aspects related to the issues mentioned above in the subsequent body of work. In the first half of my thesis, I have uncovered a role for the aPKC/Baz/Par-6 polarity protein complex in the regulation of the postsynaptic actin cytoskeleton in conjunction with the lipid and protein phosphatase PTEN. In the second half of my thesis, I have contributed to the elucidation of mechanisms underlying the secretion of Wg, the Drosophila Wnt homolog. Our findings suggest that Wnts might be secreted via a previously unidentified mechanism involving the release of exosome like vesicles from the presynapse and this process requires Evi/Wntless (Evi), a protein dedicated to Wnt secretion. Alterations in signaling pathways and aberrant cytoskeletal regulation lead to a variety of neurological disorders. The body of work in this thesis will provide a deeper understanding of the mechanisms involved in synaptic plasticity and provide a basis for uncovering similar pathways in the context of vertebrate synapses.