Serotonergic Control of Spine Morphology During Growth in Zebrafish

Abstract

Scoliosis is a three-dimensional deformity of the vertebral column that commonly emerges during growth, yet the biological mechanisms that initiate and drive curve progression remain poorly understood. Serotonin (5-hydroxytryptamine [5-HT]) has long been linked to scoliosis through its relationship with pineal melatonin signaling and through genetic associations with human disease, but its role in spinal morphogenesis has remained unclear. Here, using zebrafish, we show that serotonergic signaling is required for normal spine morphology. Transient exposure to 5-HT during development induces later spinal abnormalities, while loss of Tph2, the principal enzyme required for neuronal 5-HT synthesis, causes progressive three-dimensional spinal curvature during juvenile growth, mimicking aspects of adolescent idiopathic scoliosis (AIS). tph2 mutants undergo initially normal vertebral patterning while targeted ablation of the pineal gland does not induce scoliosis, arguing against a pineal or early skeletal origin for the 5-HT-associated spinal curves. The Reissner fiber, which has been linked to spinal curvature in zebrafish, also formed normally in tph2 mutants. Instead, mutants showed a marked reduction in Fev-expressing intraspinal serotonergic neurons together with increased locomotor activity. Mutants exhibited longer swim bouts and shorter periods of inactivity between bouts. Importantly, these motor defects were evident shortly before the onset of overt spinal curvature. Together, these findings identify neuronal serotonin as a critical regulator of spinal stability and support a model in which altered serotonergic control of motor function changes the mechanical environment experienced by the growing spine, increasing its susceptibility to progressive curvature.