PRIMARY CILIA MEDIATE THE BONE REGULATION OF LOCOMOTOR FUNCTIONS

Communication between the nervous system and muscles is essential for movement. Spinal cord motoneurons (MNs), constitute the final common pathway translating synaptic inputs into motor outputs. The loss of MNs and their reduced capacity to drive muscle contraction are major contributors to mobility decline in aging, yet the molecular signals that maintain motoneuronal integrity remain poorly understood.
Body-brain communication, mediated by circulating factors, regulate brain functions, thereby contributing to the maintenance of cognitive function with age. Among these factors, we have identified that osteocalcin (OCN), a bone-derived hormone, modulates neuronal activity during aging. Importantly, OCN levels are reduced during aging and its restoration improve motor functions in aged mice, which uncovers a novel body-spinal cord crosstalk. Mechanistically, OCN ameliorates age-related locomotor decline by autophagy. However, how spinal MNs sense hormones such as OCN remains unknown. A main gateway between systemic factors and neurons is the primary cilia, which is an extracellular antenna dedicated to sense changes in the environment. Here, we sought to investigate its role in mediating the hormonal regulation of spinal MNs and thus locomotion.
We identified the localization of OCN receptor Gpr158 in the PC of spinal cord motoneurons. We then observed that OCN regulates PC proteins and autophagy in the spinal cord. Conversely, the downregulation of PC components, including Ift88 and Ift20, impairs autophagy and motoneuronal homeostasis, as well as OCN-induction of spinal autophagy. These findings uncover a novel mechanism that controls locomotor functions and offers a therapeutic avenue to preserve motor function during aging.