Wnt signalling tunes neurotransmitter release by directly targeting Synaptotagmin-1

The functional assembly of the synaptic release machinery is well understood; however, how signalling factors modulate this process remains unknown. Recent studies suggest that Wnts play a role in presynaptic function. To examine the mechanisms involved, we investigated the interaction of release machinery proteins with Dishevelled-1 (Dvl1), a scaffold protein that determines the cellular locale of Wnt action. Here we show that Dvl1 directly interacts with Synaptotagmin-1 (Syt-1) and indirectly with the SNARE proteins SNAP25 and Syntaxin (Stx-1). Importantly, the interaction of Dvl1 with Syt-1, which is regulated by Wnts, modulates neurotransmitter release. Moreover, presynaptic terminals from Wnt signalling-deficient mice exhibit reduced release probability and are unable to sustain high-frequency release. Consistently, the readily releasable pool size and formation of SNARE complexes are reduced. Our studies demonstrate that Wnt signalling tunes neurotransmitter release and identify Syt-1 as a target for modulation by secreted signalling proteins.Fil: Ciani, Lorenza. University College London; Estados UnidosFil: Marzo, Aude. University College London; Estados UnidosFil: Boyle, Kieran. University College London; Estados UnidosFil: Stamatakou, Eleanna. University College London; Estados UnidosFil: Lopes, Douglas M.. University College London; Estados UnidosFil: Anane, Derek. University College London; Estados UnidosFil: McLeod, Faye. University College London; Estados UnidosFil: Rosso, Silvana Beatriz. University College London; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gibb, Alasdair. University College London; Estados UnidosFil: Salinas, Patricia C.. University College London; Estados Unido

Versatile, Highly Controlled Synthesis of Hybrid (Meth)acrylate–Polyester–Carbonates and their Exploitation in Tandem Post-Polymerization–Functionalization

The use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a mild catalyst for the ring-opening polymerization (ROP) of the pharma-friendly and biodegradable monomer lactide and a functionalizable tert-butyloxycarbonyl (BOC)-protected cyclic carbonate is explored. Successful and controlled ROP is demonstrated when employing a series of labile-ester (bis)(meth)acrylate initiators to produce macromonomers suitable for a range of post-polymerization modifications. Importantly, the use of DBU ensured retention of the BOC group of the carbonate monomer during the polymerization, thus facilitating the production of highly functionalizable hybrid materials unobtainable using the more reactive triazabicyclodecene (TBD). Subsequently, a variety of short homo- and copolymers are synthesized with good control over material properties and final polymer composition. Successful attainment of these short copolymers confirm that DBU can overcome the previously observed limitations of TBD related to its kinetic competition between ROP and transesterification side-reactions under these reaction conditions. Furthermore, the fidelity of the hydroxyl and (meth)acrylic end groups are maintained as confirmed by a series of secondary tandem reactions. The macromonomers are also utilized in reversible addition−fragmentation chain-transfer polymerization (RAFT) polymerization for the production of amphiphilic block or random copolymers with a hydrophilic comonomer, poly(ethyleneglycol)methacrylate. The amphiphilic copolymers produced via the tandem RAFT reaction demonstrate the ability to self-assemble into monodisperse nanoparticles in aqueous environments.</p