Molecular Dissection of Proprioceptor Subclass Identity

SUMMARY The proprioceptive sense relies on multiple sensory subtypes that relay information from skin, joint, or muscle, to best estimate changes in limb dynamics. Proprioceptive muscle afferents - arguably representing the primary input into this sensory system – derive their sensory feedback information from two specialized mechano- receptive end-organs in skeletal muscle: muscle spindles (MSs), and Golgi tendon organs (GTOs). These end- organs respond to changes in muscle length or tension, respectively, and this information is routed to spinal and supraspinal motor centers through MS-groups Ia and II afferents, and GTO-group Ib afferents, which each relay qualitatively distinct features of limb state (e.g., movement speed, position, effort). The combined afferent feedback is used by central somatosensory and motor circuits to compute changes in limb state during passive or voluntary movement, and to correct the motor plan if needed. Despite their importance in movement control, how individual proprioceptor subtypes emerge during development remains poorly understood. Two opposing ideas are considered. First, it has been postulated that proprioceptive muscle afferent subtypes are genetically predetermined, meaning that their MS-group Ia or II, or GTO-group Ib identity, is fixed from the moment these neurons become post-mitotic. Recent data however, including from our lab, have led to the hypothesis that proprioceptive neurons adopt their specific subtype identity only after they innervate their cognate peripheral receptors, possibly instructed by signals from nascent MS or GTO end-organs or through activity-dependent mechanisms. This proposal aims to test this idea through three parallel aims that examine intrinsic proprioceptor transcriptomic and epigenetic dynamics i) prior to and just following end-organ innervation, ii) in the absence of extrinsic end-organs derived signals, or iii) when neural activity is compromised. Together, these experiments will identify the transcriptional and epigenetic signatures of proprioceptors as they undergo their developmental transitions to assume MS- or GTO-afferent subtype identities, and provide insight into the relevant signals that are needed to coordinate this process or to maintain these identities. The results should lead to an expansion of the genetic and molecular tools to study proprioceptor function. Moreover, given recent demonstrations that epidural stimulation of proprioceptive pathways benefits patients suffering from spinal cord injury, a better understanding of the developmental cues that promote one proprioceptor subtype over another may permit the selective stimulation/repurposing of those proprioceptor subtypes that are especially beneficial for recovery.