NATRIURETIC PEPTIDE C RECEPTOR 3 CONTRIBUTES TO AXIAL MORPHOGENESIS IN VERTEBRATES

Spinal deformities, such as scoliosis and kyphosis, are associated with multiple genetic risk factors. In particular, the natriuretic receptor (npr3) has been involved with adolescent idiopathic scoliosis (AIS). Yet, underlying mechanisms are not well understood. Previous studies showed that molecular signaling at the interface with the cerebrospinal fluid (CSF) in the spinal cord involves ciliated neurons with the Reissner Fiber that together contribute to postembryonic spine morphogenesis. Here, we show that npr3 Danio rerio mutants display very specific morphogenetic defects: npr3 mutant larvae display left or right curvature confined to the horizontal plane. In npr3 adult zebrafish mutants, deformations occur in the caudal spine as 3D deformations of the spine. Remarkably, npr3 Xenopus laevis mutant tadpoles also developed axial deformities by NF stages 47-50, indicating a conserved role for npr3 in anamniote axial development. In fish and frogs, we show that npr3 is expressed in spinal CSF-contacting neurons and floor plate cells. In zebrafish mutants, the Reissner fiber is intact, indicating that defects occur downstream. Calcium imaging performed on 2- and 5-day old zebrafish larvae revealed in npr3 crispants reduced activity in CSF-contacting neurons, while floor plate cell activity is enhanced compared to control siblings. Our findings point towards a dysregulation of sensory signaling, involving both ciliated neurons and floor plate cells at the interface with the CSF associated with deformities in npr3 mutants during postembryonic development. Future research will investigate how this signaling pathways contributes to maintain a proper body alignment.