SEROTONIN SIGNALLING IN THE CENTRAL NERVOUS SYSTEM IS REQUIRED FOR CORRECT SPINE MORPHOGENESIS IN ZEBRAFISH

Although adolescent idiopathic scoliosis (AIS) affects over 1% of children and teenagers worldwide, its genetic causes are not fully understood. Recently, defects in serotoninergic system have been associated with certain familial cases of AIS, but the underlying causes remain elusive. Over the last decade, zebrafish has emerged as an optimal model to study mechanisms underlying deformations of the spine. In animal models, ciliary disfunctions, sensory feedback and the Reissner fibre have been shown to play an instrumental role for maintaining a straight body axis.
We show that in tph2 mutant zebrafish, serotonin depletion causes progressive 3D spine misalignment mimicking human AIS. Mutant larvae develop normally until 21 days post-fertilization (dpf), when curvatures emerge during the growth spurt, recapitulating AIS onset in humans. As in human AIS, deformities of zebrafish tph2 mutant worsen with age in both sagittal and coronal planes, without vertebral malformations. In tph2 mutant larvae, the Reissner fibre remains intact, yet serotonin is completely absent from the spinal cord. Intraspinal serotonergic neurons are gradually depleted up to scoliosis onset, together with supraspinal projections from the inferior raphe, eliminating all sources of serotonin in the spinal cord by 21 dpf. These findings reveal that serotonin plays an essential role in maintaining body axis alignment during morphogenesis and suggest that spinal signalling is necessary for proper spine alignment during post-embryonic development.