Linking an activity-dependent BMP pathway to synapse structure and function

Project Summary The vast majority of our understanding regarding the function of classical developmental signaling pathways comes from studies outside the nervous system. We are interested in the overarching question of how evolutionarily conserved signaling pathways are customized for signaling at synapses. There are significant unanswered questions regarding how these pathways interface with synaptic activity as well as how they signal in the dense microenvironment of the synaptic cleft. Our identification of Crimpy and α2δ-3 as two novel components of a synaptic Bone Morphogenetic Protein (BMP) signaling pathway provides key insights into both questions, positioning us to explore innovative hypotheses directed at understanding how growth factors organize synapses. Our published studies indicate that autocrine BMP signaling assembles multiple principal features of the presynaptic compartment. Here, we build on novel findings relating to the regulation and function of this pathway. We provide evidence that autocrine BMP signaling maintains trans-synaptic adhesion and alignment of the pre- and postsynaptic compartments. Shedding light on these phenotypes, we identified the ECM protein SPARC as a putative BMP downstream effector. Lastly, we present novel preliminary data that the ability of this pathway to nucleate new presynaptic active zones is impeded by a transmembrane protein in the LRIG family.