Abnormal Cerebrospinal Fluid Flow: A New Model of Idiopathic Scoliosis.

A s its name suggests, idiopathic scoliosis (IS) is a diagnosis made with unknown pathological factors that could give rise to observed scoliotic changes. It has been reported at rates of 3% to 5.2% in pediatric and adolescent populations and occurs more frequently in females than males (3:1). Disease progression and sequelae are largely a function of the location and severity of scoliotic curves, as well as the rate and manner in which these curves change over time. For example, curves in the thoracic spine have been reported as most vulnerable to progression and can cause cardiovascular or pulmonary pathology. Early detection has proven beneficial in patients treated conservatively (eg, bracing or casting) and surgically. However, as long as the cause of IS remains unknown, therapy can be initiated only after the scoliotic changes have begun, eliminating the opportunity for physicians to prevent these deformities from developing at all. With a series of experiments, a joint team including researchers at Princeton University and the University of Toronto has recently identified a possible pathogenic mechanism for IS in zebrafish as a model for human spinal development. Their data show that mutations in protein tyrosine kinase-7 (ptk7, a signaling pathway regulator) impair the growth and function of ependymal cell (EC) cilia, preventing the proper flow of cerebrospinal fluid (CSF). Importantly, these mutations and CSF flow irregularities are directly associated with deformities in the developing spine that parallel the human manifestations of IS. CSF flow during development is normally driven by the polarized beating of EC cilia. Therefore, the team first examined EC surface morphology under scanning electron microscopy, comparing cells from zebrafish sibling pairs: 1 fish was a scoliotic ptk7 mutant (ptk7), the other a ptk7-normal nonscoliotic control (ptk7/1). Although the control group had a normal distribution and arrangement of EC cilia, ptk7mutants generally lacked EC cilia, and the few present cilia were disorganized and lacked polarization. The mutants also showed signs of hydrocephalus, which is typically associated with impaired EC cilia function and CSF flow abnormalities (Figure). Furthermore, by placing fluorescent microspheres across the EC surface, the team observed robust anterior-posterior flow in the ptk7-normal controls. In contrast, what little motion was observed in the ptk7mutants was both erratic and significantly slower. In an attempt to show that IS develops directly from ptk7-related EC ciliary dysfunction, the team next used a transcription factor (foxJ1a) to restore ptk7 specifically in the midline structures of the brain and spinal cord in mutant lines. The mutants that were reintroduced ptk7 (ptk7 1 Tg [foxj1a::ptk7]) developed normal EC ciliary function, organized CSF flow, and no hydrocephalus. Furthermore, microcomputed tomography in these lines showed normal spine development with no scoliotic curves. Having shown that IS was caused by ptk7 mutation, the consequent loss of EC motile cilia, and ultimately CSF flow defect, the team investigated other mutations that impair cilia development or function and so should in theory cause IS. However, these mutations generally cause death in the first 1 to 2 weeks of embryonic development, making their downstream effects on spinal development impossible to assess. To avoid early embryonic death, the