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 peripheral muscle targets. Motor neurons are activated by a precisely regulated pattern of synaptic activity from sensory neurons, local spinal interneurons and descending pathways from the brain. Additionally, synaptic activity received by motor neurons during early development shapes their functional properties. In contrast, gene mutations that induce perturbations in either neuronal wiring or synaptic drive received by motor neurons often result in motor system disorders, although the primary cellular targets and the precise molecular events remain 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 challenges in neurobiology. A prominent example of this situation is spinal muscular atrophy (SMA)—an inherited neuromuscular disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. SMA pathogenesis involves alterations of multiple components of the motor circuit leading to abnormalities in spinal reflexes, motor neuron loss and skeletal muscle atrophy. However, the molecular and cellular mechanisms underlying motor circuit dysfunction in SMA remain poorly understood. In our previous work we have identified 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. Building on these findings, our goal is to define the neural circuit components and cellular pathway(s) in which Stasimon functions that underlie its essential role in the motor circuit and contribution to human disease. To do so, we will employ newly developed conditional mice for cell type-specific restoration of Stasimon in vivo to study whether Stasimon dysfunction induced by SMN deficiency acts cell autonomously 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, w...