Motor circuits control fundamental behaviors such as swallowing, breathing and locomotion. Spinal motor neurons are the key mediators translating motor commands generated within the central nervous system to peripheralmuscletargets.Motorneuronsareactivatedbyapreciselyregulatedpatternofsynapticactivityfrom sensory neurons, local spinal interneurons and descending pathways from the brain. Additionally, synaptic activityreceivedbymotorneuronsduringearlydevelopmentshapestheirfunctionalproperties.Incontrast,gene mutationsthatinduceperturbationsineitherneuronalwiringorsynapticdrivereceivedbymotorneuronsoften resultinmotorsystemdisorders,althoughtheprimarycellulartargetsandtheprecisemoleculareventsremain largely elusive. Thus, understanding the principles of neural circuit development and function as well as the mechanisms of synaptic dysfunction and selective neuronal death in human disease represent outstanding challengesinneurobiology.Aprominentexampleofthissituationisspinalmuscularatrophy(SMA)?aninherited neuromuscular disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. SMA pathogenesisinvolvesalterationsofmultiplecomponentsofthemotorcircuitleadingtoabnormalitiesinspinal reflexes, motor neuron loss and skeletal muscle atrophy. However, the molecular and cellular mechanisms underlyingmotorcircuitdysfunctioninSMAremainpoorlyunderstood.Inourpreviousworkwehaveidentified Stasimon as a novel transmembrane protein that localizes at contacts sites between ER and mitochondria membranes and contributes to motor dysfunction in animal models of SMA through undefined mechanisms. Furthermore, our preliminary studies revealed that Stasimon?s conditional depletion in neural circuits severely disrupts motor function in mouse models, pointing to an essential requirement for normal motor system development and function. Buildingon these findings, our goal is to define theneural circuit components and cellularpathway(s)inwhichStasimonfunctionsthatunderlieitsessentialroleinthemotorcircuitandcontribution tohumandisease.Todoso,wewillemploynewlydevelopedconditionalmiceforcelltype-specificrestoration ofStasimoninvivotostudywhetherStasimondysfunctioninducedbySMNdeficiencyactscellautonomously to promote death of SMA motor neurons and non-cell autonomously to alter motor neuron firing through dysfunction of proprioceptive sensory neurons (Aim 1). We will also investigate the temporal and spatial requirement of Stasimon for normal development and function of the sensory-motor circuit using novel conditional knockout mice we have recently developed (Aim 2). Lastly, we will use both cellular and mouse modelstocharacterizethemolecularfunctionofStasimonattheER-mitochondriacontactsanditsrequirement formotorcircuitfunctioninhealthanddisease(Aim3).Thesuccessfulaccomplishmentoftheobjectivesofthis proposal will characterize novel aspects of synaptic transmission and motor circuit function as well as the underlyingmechanismsofSMA.
Neuronalcontrolofmovementisextensivelystudiednotonlybecauseitunderliesfundamentalhumanbehaviors but also because diseases that affect the motor system represent a significant burden for human health. StasimonisanER--residenttransmembraneproteinwithanimportantyetmolecularlyundefinedroleinhealth and disease of the motor system. This proposal describes a multidisciplinary effort aimed to establish the essentialrequirementofStasimonformotorfunctionanditscontributiontotheneurodegenerativediseaseSMA atthemolecular,cellularandcircuitlevels.