The role of Frizzled receptors in the assembly of central synapses.
Lead Research Organisation:
University College London
Department Name: Cell and Developmental Biology
Abstract
The formation of a functional brain requires the assembly of appropriate nerve connections. During development, nerve cells (neurons) extend long processes called axons in search for their target to subsequently form connections (synapses). Synapses contain two main components, the presynaptic terminal that releases neurotransmitter and the postsynaptic terminal (in the target) that is receptive to neurotransmitters so that an electrical impulse is transmitted from one terminal (presynaptic) to another neurons (the postsynaptic terminal). After reaching their targets, axons receive signals that stimulate the assembly of synapses. However, the mechanisms by which nerve cells interpret these signals to initiate the assembly of the machinery involved in neurotransmitter release remains poorly understood. Our laboratory has been studying the function of Wnts, molecules released by synaptic targets, in the formation of nerve connections in the mammalian brain. Wnts induce the recruitment of key molecules to specific areas of the axon resulting in the formation of functional synapses. However, the mechanisms that control where synapses are formed remain poorly understood. This proposal addresses the mechanisms by which neurons respond to signals to assembly synapses at the right place. Using neuronal cell cultures and mutant mice, we plan to examine how extracellular signals called Wnts are interpreted by receptive cells to stimulate the formation and maintenance of synapses at specific locations. New studies suggest that neuronal cell loss observed in neurodegenerative diseases such as Parkinson and Alzheimer?s are trigged by the loss of synapses. Therefore, understanding the mechanisms that regulate how synapse are formed and maintained is crucial for the development of therapeutic strategies for the treatment and/or prevention of neuronal degeneration.
Technical Summary
The elucidation of the molecular mechanisms that regulate the formation and maintenance of synapses is central for understanding how complex neuronal circuits are formed and modulated during the life of the organism. Furthermore, comprehension of these molecular principles is crucial for the development of therapeutic approaches for nerve and brain regeneration after injury or disease.
Great progress has been made in the identification of some of the signals that regulate synapse formation. Several labs, including ours, have identified signalling molecules that regulate the assembly and maturation of synapses. However, the specific molecular mechanisms and signalling pathways that lead to the recruitment of synaptic components to future synaptic sites is poorly understood. Our lab has demonstrated that members of the Wnt family regulate neuronal circuit formation by acting as target-derived factors that regulate the terminal remodelling of axons and synapse formation. Still, the mechanisms triggered by Wnt to promote synapse formation are not well characterized. Although Wnt signalling regulates the recruitment of synaptic proteins to future synaptic sites, it is unclear what determines where synapses form and what signalling cascade induces protein recruitment to future synaptic sites. The central aim of this proposal is to elucidate the function of Frizzled, the Wnt receptors, and associated molecules in the assembly of synapses in the hippocampal system. Using gain and loss of function studies in cultured neurons and in vivo animal models, we plan to examine the contribution of Wnt ligands in the distribution of Fz receptors in relation to synaptic sites and how activation of Fz receptors leads to the recruitment of synaptic components. We will also examine the role of Wnt-Fz signalling in synaptic maintenance in mature neurons. Several studies suggest that neuronal cell loss in neurodegenerative diseases is due to the loss of synaptic contacts. Therefore, understanding the mechanisms that regulate synapse formation might shed light into possible therapeutic strategies for the treatment and/or prevention of neuronal degeneration.
Great progress has been made in the identification of some of the signals that regulate synapse formation. Several labs, including ours, have identified signalling molecules that regulate the assembly and maturation of synapses. However, the specific molecular mechanisms and signalling pathways that lead to the recruitment of synaptic components to future synaptic sites is poorly understood. Our lab has demonstrated that members of the Wnt family regulate neuronal circuit formation by acting as target-derived factors that regulate the terminal remodelling of axons and synapse formation. Still, the mechanisms triggered by Wnt to promote synapse formation are not well characterized. Although Wnt signalling regulates the recruitment of synaptic proteins to future synaptic sites, it is unclear what determines where synapses form and what signalling cascade induces protein recruitment to future synaptic sites. The central aim of this proposal is to elucidate the function of Frizzled, the Wnt receptors, and associated molecules in the assembly of synapses in the hippocampal system. Using gain and loss of function studies in cultured neurons and in vivo animal models, we plan to examine the contribution of Wnt ligands in the distribution of Fz receptors in relation to synaptic sites and how activation of Fz receptors leads to the recruitment of synaptic components. We will also examine the role of Wnt-Fz signalling in synaptic maintenance in mature neurons. Several studies suggest that neuronal cell loss in neurodegenerative diseases is due to the loss of synaptic contacts. Therefore, understanding the mechanisms that regulate synapse formation might shed light into possible therapeutic strategies for the treatment and/or prevention of neuronal degeneration.
