Chiari II brain malformation is secondary to open spina bifida

Chiari II brain malformation affects 90% of children with open spina bifida. Hindbrain herniation leads to hydrocephalus, together with higher-brain anomalies including cerebral cortical defects implicated in learning disability, which affects 20-25% of children with spina bifida. The causal link between Chiari II and spina bifida has long been debated, and we aimed to determine whether Chiari II arises secondary to spina bifida, rather than as a separate effect of shared genetic or non-genetic factor(s). Pax3 gene function was conditionally deleted by Cdx2cre specifically in the lower body of mice, leaving the head genetically intact. Open spina bifida was seen in all Cdx2cre/+;Pax3fl/fl fetuses, together with many features of Chiari II in the wild-type brain and skull. These included hindbrain herniation, callosal and hippocampal hypogenesis, cortical thinning with neuronal heterotopia, a thickened ventricular zone and posterior skull defects. Hence, the brain and skull defects of Chiari II arise secondary to open spina bifida, with likely disturbance of neurogenesis and neuronal migration early in gestation. The Cdx2cre/+;Pax3fl/fl mouse provides a model for improved understanding of Chiari II pathogenesis.