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.

Grant Number: 5R01NS095895-10
NIH Institute/Center: NIH
Principal Investigator: Heather Broihier