Congenital Hydrocephalus in Genetically Engineered Mice

Abstract

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 ciliarelated 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.

Multiple roles of Ulk4 in neurogenesis and brain function

“…25 Remarkably, mutations of Celsr2, Fzd3, Ulk4 and Stk36 are all found as risk factors of congenital hydrocephalus. 27 We show that Ulk4 deficiency impairs cilia formation and function, leading to hydrocephalus. This may be mediated by dysregulated Foxj1 and Wnt signaling.…”

Recurrent deletions of ULK4 in schizophrenia: a novel gene crucial for neuritogenesis and neuronal motility

“…Recent GWAS studies suggest it is a risk locus for multiple myeloma (Broderick et al, 2011) and interindividual diastolic blood pressure variation (Levy et al, 2009). Null mice with targeted deletion of Ulk4 were recently reported to develop congenital hydrocephalus, and their respiratory epithelia and ependymal cells had shorter cilia than normal, indicating ciliopathies (Vogel et al, 2012). Intriguingly, many imaging studies have suggested that schizophrenia patients have increased global or regional cerebrospinal fluid (Ananth et al, 2002;Bose et al, 2009;Hulshoff Pol et al, 2002).…”

An update on research priorities in hydrocephalus: overview of the third National Institutes of Health-sponsored symposium “Opportunities for Hydrocephalus Research: Pathways to Better Outcomes”

“…Early pattern formation genes such as SHH, ZIC2, PAX6, and WNT1, neuronal path-finding genes such as L1CAM, genes related to cortical development such as POMT1, and those related to growth regulation such as PIK3CA and AKT3 have been implicated. 1,3,7,10,29,52,53,72,84,85,91,103,122 Developmental disorders presenting with hydrocephalus include neural tube disorders, forebrain and hindbrain developmental disorders, brain growth disorders, and cortical malformations. Alterations in the choroid plexus, ependyma, aqueduct, ventricles, and extraaxial spaces can also lead to hydrocephalus.…”