Chiari II brain malformation is secondary to open spina bifida

Chiari II brain malformation affects 90% of children with open spina bifida. The hindbrain herniates into the vertebral canal leading to hydrocephalus and occasional respiratory emergency. Chiari II is not confined to the hindbrain, but is a global brain syndrome with cerebral cortical defects implicated in learning disability, which affects 20-25% of children with open spina bifida. The reason for the association between Chiari II and spina bifida has long been debated: causative genetic or non-genetic factor(s) might cause the cranial and spinal defects separately, or Chiari II might arise secondary to open spina bifida. To resolve this question, we bred mice in which Pax3 gene function is conditionally deleted by Cdx2 ^cre specifically in the lower body, leaving the head genetically intact. Open spina bifida is seen in all Cdx2 ^cre/+ ; Pax3 ^fl/fl fetuses, together with many features of Chiari II in the wild-type brain. These include: hindbrain herniation, callosal and hippocampal hypogenesis, cortical thinning with neuronal heterotopia, and a thickened ventricular zone. We conclude that the brain defects of Chiari II arise secondary to open spina bifida, likely as a result of disturbed neurogenesis early in gestation. The Cdx2 ^cre/+ ; Pax3 ^fl/fl mouse provides a model for improved understanding of Chiari II pathogenesis.