Abstract
Congenital hydrocephalus results from cerebrospinal fluid accumulation in the ventricles of the brain and causes severe neurological damage, but the underlying causes are not well understood. It is associated with several syndromes, including primary ciliary dyskinesia (PCD), which is caused by dysfunction of motile cilia. We previously demonstrated that mouse models of PCD lacking ciliary proteins CFAP221, CFAP54 and SPEF2 all have hydrocephalus with a strain-dependent severity. While morphological defects are more severe on the C57BL/6J (B6) background than 129S6/SvEvTac (129), cerebrospinal fluid flow is perturbed on both backgrounds, suggesting that abnormal cilia-driven flow is not the only factor underlying the hydrocephalus phenotype. Here, we performed a microarray analysis on brains from wild type and nm1054 mice lacking CFAP221 on the B6 and 129 backgrounds. Expression differences were observed for a number of genes that cluster into distinct groups based on expression pattern and biological function, many of them implicated in cellular and biochemical processes essential for proper brain development. These include genes known to be functionally relevant to congenital hydrocephalus, as well as formation and function of both motile and sensory cilia. Identification of these genes provides important clues to mechanisms underlying congenital hydrocephalus severity.
Highlights
Hydrocephalus is a complex disorder with both genetic and environmental causes[1]
Hydrocephalus is associated with a variety of genetic syndromes, including Dandy-Walker syndrome, Walker-Warburg syndrome, Noonan syndrome, Joubert syndrome and primary ciliary dyskinesia[1,7,16]
We have demonstrated that congenic mouse models of Primary ciliary dyskinesia (PCD) lacking ciliary proteins CFAP221, CFAP54 and SPEF2 all have a severe hydrocephalus on the C57BL6/J (B6) background but not on 129S6/SvEvTac (129) or a mixed (B6x129)F1 background[20,21,22], indicating strain specificity in susceptibility to severe PCD-associated hydrocephalus
Summary
Hydrocephalus is a complex disorder with both genetic and environmental causes[1]. It results from accumulation of cerebrospinal fluid (CSF) in the ventricles of the brain that typically leads to ventricular enlargement, damage to the underlying ependyma and white matter and thinning of the cerebral cortex[2,3]. While there are defects in cilia-driven fluid flow on both backgrounds, ventricular dilatation and secondary damage to surrounding brain tissue are consistently more severe in mutants on the B6 background[23] These findings are consistent with reports of severe hydrocephalus in other PCD models on the B6 background and an absence of severe hydrocephalus in models on the 129 background[16]. We analyzed gene expression levels in brains from wild type and nm1054 mice on the B6 and 129 backgrounds and identified strain-specific expression levels for a number of genes that cluster into distinct groups based on expression profile and biological function These genes are implicated in a variety of cellular and biochemical processes essential for proper brain development, including several with known relevance to hydrocephalus and ciliogenesis, providing the first insight into pathways that may underlie susceptibility to severe congenital hydrocephalus
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