Congenital Hydrocephalus in Genetically Engineered Mice

There is evidence that genetic factors play a role in the complex multifactorial pathogenesis of hydrocephalus. Identification of the genes involved in the development of this neurologic disorder in animal models may elucidate factors responsible for the excessive accumulation of cerebrospinal fluid in hydrocephalic humans. The authors report here a brief summary of findings from 12 lines of genetically engineered mice that presented with autosomal recessive congenital hydrocephalus. This study illustrates the value of knockout mice in identifying genetic factors involved in the development of congenital hydrocephalus. Findings suggest that dysfunctional motile cilia represent the underlying pathogenetic mechanism in 8 of the 12 lines (Ulk4, Nme5, Nme7, Kif27, Stk36, Dpcd, Ak7, and Ak8). The likely underlying cause in the remaining 4 lines (RIKEN 4930444A02, Celsr2, Mboat7, and transgenic FZD3) was not determined, but it is possible that some of these could also have ciliary defects. For example, the cerebellar malformations observed in RIKEN 4930444A02 knockout mice show similarities to a number of developmental disorders, such as Joubert, Meckel-Gruber, and Bardet-Biedl syndromes, which involve mutations in cilia-related genes. Even though the direct relevance of mouse models to hydrocephalus in humans remains uncertain, the high prevalence of familial patterns of inheritance for congenital hydrocephalus in humans suggests that identification of genes responsible for development of hydrocephalus in mice may lead to the identification of homologous modifier genes and susceptibility alleles in humans. Also, characterization of mouse models can enhance understanding of important cell signaling and developmental pathways involved in the pathogenesis of hydrocephalus.