Abstract
BackgroundCirculation of cerebrospinal fluid (CSF) through the ventricular system is driven by motile cilia on ependymal cells of the brain. Disturbed ciliary motility induces the formation of hydrocephalus, a pathological accumulation of CSF resulting in ventricle dilatation and increased intracranial pressure. The mechanism by which loss of motile cilia causes hydrocephalus has not been elucidated. The aim of this study was: (1) to provide a detailed account of the development of ciliation in the brain of the African clawed frog Xenopus laevis; and (2) to analyze the relevance of ependymal cilia motility for CSF circulation and brain ventricle morphogenesis in Xenopus.MethodsGene expression analysis of foxj1, the bona fide marker for motile cilia, was used to identify potentially ciliated regions in the developing central nervous system (CNS) of the tadpole. Scanning electron microscopy (SEM) was used to reveal the distribution of mono- and multiciliated cells during successive stages of brain morphogenesis, which was functionally assessed by bead injection and video microscopy of ventricular CSF flow. An antisense morpholino oligonucleotide (MO)-mediated gene knock-down that targeted foxj1 in the CNS was applied to assess the role of motile cilia in the ventricles.ResultsRNA transcripts of foxj1 in the CNS were found from neurula stages onwards. Following neural tube closure, foxj1 expression was seen in distinct ventricular regions such as the zona limitans intrathalamica (ZLI), subcommissural organ (SCO), floor plate, choroid plexus (CP), and rhombomere boundaries. In all areas, expression of foxj1 preceded the outgrowth of monocilia and the subsequent switch to multiciliated ependymal cells. Cilia were absent in foxj1 morphants, causing impaired CSF flow and fourth ventricle hydrocephalus in tadpole-stage embryos.ConclusionsMotile ependymal cilia are important organelles in the Xenopus CNS, as they are essential for the circulation of CSF and maintenance of homeostatic fluid pressure. The Xenopus CNS ventricles might serve as a novel model system for the analysis of human ciliary genes whose deficiency cause hydrocephalus.
Highlights
Circulation of cerebrospinal fluid (CSF) through the ventricular system is driven by motile cilia on ependymal cells of the brain
Transcripts were absent from the archencephalon, which will give rise to the forebrain and is situated dorsally to the prechordal plate at stage 20 (Figure 1B, C). foxj1 signals persisted in the floor plate of the spinal cord throughout embryonic development (Figure 1D-G, outlined arrowheads in D’-F’)
Congenital hydrocephalus has been attributed to a loss of ciliary motility in the brain ventricles and the consequential loss of CSF movement
Summary
Circulation of cerebrospinal fluid (CSF) through the ventricular system is driven by motile cilia on ependymal cells of the brain. The aim of this study was: (1) to provide a detailed account of the development of ciliation in the brain of the African clawed frog Xenopus laevis; and (2) to analyze the relevance of ependymal cilia motility for CSF circulation and brain ventricle morphogenesis in Xenopus. Mice deficient in Mdnah5 [7] for example have no detectable ependymal flow, leading to stenosis of the cerebral aqueduct and hydrocephalus in the lateral and third ventricles [5,7]. Loss of Foxj function leads to a loss of motile, but not immotile cilia [9,10,11,12], and Foxj knock-out mice develop hydrocephalus postnatally [10,11]. Transcription of Foxj marks the onset of ciliogenesis in all embryonic tissues studied so far, rendering Foxj a bona fide marker gene for motile cilia [9]
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