Determining the role of serotonin synthesis in neuronal architecture and spine morphology

About This Grant

Project Summary/Abstract Scoliosis is a complex disorder characterized by abnormal curvature of the spine, often emerging during adolescence and resulting in long-term health and mobility challenges. Current treatments, including bracing, physical therapy, and surgery, are limited in effectiveness and do not address underlying causes. Despite its prevalence, the biological mechanisms that drive scoliosis remain poorly understood, hindering efforts to develop predictive tools or targeted therapies. Variants in serotonin synthesis pathways and decreased serotonin levels have been associated with scoliosis, yet the mechanistic links remain unclear. This project addresses that gap using a zebrafish model carrying a loss-of-function mutation in tph2, which encodes the rate-limiting enzyme for neuronal serotonin synthesis. Preliminary observations indicate that tph2-null zebrafish develop spinal curves, exhibit disrupted motor neuron architecture, and show altered locomotor behavior. The central hypothesis is that serotonin modulates motor neuron development and bilateral locomotor output, which in turn influence spine morphology through biomechanical forces during growth. Aim 1 will define the requirement and cellular source of tph2 for motor neuron development, using pharmacological rescue, cell-type-specific transgenics, and in vivo imaging. Aim 2 will determine how bilateral locomotor patterning contributes to spine morphogenesis, using high-speed kinematic analysis, selective motor neuron ablation, and manipulation of neuronal signaling. This work will establish a mechanistic link between serotonergic signaling, motor output, and spine development, offering new insight into the neurobiological basis of scoliosis. More broadly, it will illuminate how neural activity contributes to body shape, an emerging and understudied aspect of vertebrate development. The proposed fellowship includes structured training in behavioral neuroscience and biomechanics, supported by a multidisciplinary mentorship team with expertise in zebrafish genetics, motor circuitry, biophysics, musculoskeletal bioengineering, and clinical scoliosis research. This training environment will support the development of a scientist prepared to lead independent research at the interface of developmental biology, neurobiology, and human disease.