Absence of posterior commissure and sub-commissural organ precedes encephalocele development in a new mouse model

Encephalocele is a congenital defect involving herniation of the meninges, with or without brain tissue, outside the skull. Although traditionally considered a neural tube defect (NTD) alongside anencephaly and open spina bifida (myelomeningocele), encephalocele typically shows well-formed brain tissue, and is likely to represent a later-arising, post-neurulation developmental anomaly, with a different pathogenic mechanism from the open NTDs. A detailed understanding of encephalocele pathogenesis requires experimental studies and, recently, we developed a new mouse model in which the genes encoding FGF3, 4 and 15 are over-expressed in the embryonic day (E) 9.5 brain. Encephalocele subsequently develops as a broad forebrain-midbrain swelling, visible from E11.5, that resolves by birth into a focal brain herniation resembling human parieto-occipital encephalocele. A structural analysis of the brain in mutant embryos reveals absence of the posterior commissure and sub-commissural organ, and at later stages the pineal gland. These structures normally develop just rostral to the forebrain-midbrain boundary, and Pax6 immuno-histochemistry demonstrates that this boundary remains intact in the mutant embryos. Histological analysis reveals a more general change in tissue composition of the neural tube roof in the forebrain-midbrain region, with diminished thickness of the neuroepithelium and increased thickness of the overlying layer, including the non-neural ectoderm (future epidermis). We conclude that the posterior commissure and sub-commissural organ, previously implicated in hydrocephalus, may also be fundamental for development of the earlier-arising brain malformation, encephalocele.