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Scoliosis linked to disruptions in spinal fluid flow

A new study in zebrafish suggests that irregular fluid flow through the spinal column brought on by gene mutations is linked to a type of scoliosis that can affect humans during adolescence. Found in humans and zebrafish, these mutated genes damage the cilia – tiny hair-like projections that line the spinal canal and help move the fluid – and lead to a curvature of the spine.

The researchers found that when they repaired the mutated cilia genes, they restored cerebrospinal fluid flow and could prevent spinal curves from developing. If translatable to humans, the study could lead to a non-surgical approach for treating the condition known as idiopathic scoliosis, which has no known cause and affects roughly three out of every 100 adolescents. The research was published by the journal Science by researchers at Princeton University and the University of Toronto.

“This is the first hint of a biological mechanism for idiopathic scoliosis,” said Rebecca Burdine, associate professor of molecular biology at Princeton, and a senior author of the study. “We hope this research will open up new areas of inquiry as to how the disruptions to normal cerebrospinal fluid flow can lead to spinal curvature.”

Burdine’s lab conducted the study in collaboration with a team led by senior author Brian Ciruna, an associate professor of molecular genetics at the University of Toronto and a senior scientist at the Hospital for Sick Children in Toronto.

“Traditionally, theories regarding the biology behind idiopathic scoliosis have revolved around defects in the bone, cartilage or neuromuscular activity,” Ciruna said. “The finding that defects in cerebrospinal fluid flow may be contributing to scoliosis came as a surprise. It is not a theory that had been put out there previously.”

The study is the first to link spinal curvature to mutations in genes that govern motile cilia, which stick out from cells and make synchronous whip-like motions to push fluid through narrow passages such as the spinal column.

Hazel Sive, a professor in biology at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology who was not involved in the study, is an expert in the use of zebrafish to study vertebrate development.

“This study is an important step forward in understanding events underlying spinal curvature,” Sive said. “In an elegant set of experiments, the authors take advantage of the outstanding zebrafish system to define that cilia function and perhaps cerebrospinal fluid flow is required for normal spinal cord development.”

Researchers in the Burdine laboratory had observed that mutant genes that disrupt cilia motility produce spinal curves in zebrafish as adults, although the work had not been published. “I’ve presented this finding for years, but didn’t have a way to link this work to human disease,” Burdine said. “Collaborating with Brian’s group helped us make this link.”