Abstract

Hydrocephalus is a brain disorder triggered by cerebrospinal fluid accumulation in brain cavities. Even though cerebrospinal fluid flow is known to be driven by the orchestrated beating of the bundled motile cilia of ependymal cells, little is known about the mechanism of ciliary motility. RSPH9 is increasingly becoming recognized as a vital component of radial spokes in ciliary “9 + 2” ultrastructure organization. Here, we show that deletion of the Rsph9 gene leads to the development of hydrocephalus in the early postnatal period. However, the neurodevelopment and astrocyte development are normal in embryonic Rsph9−/− mice. The tubular structure of the central aqueduct was comparable in Rsph9−/− mice. Using high-speed video microscopy, we visualized lower beating amplitude and irregular rotation beating pattern of cilia bundles in Rsph9−/− mice compared with that of wild-type mice. And the centriolar patch size was significantly increased in Rsph9−/− cells. TEM results showed that deletion of Rsph9 causes little impact in ciliary axonemal organization but the Rsph9−/− cilia frequently had abnormal ectopic ciliary membrane inclusions. In addition, hydrocephalus in Rsph9−/− mice results in the development of astrogliosis, microgliosis and cerebrovascular abnormalities. Eventually, the ependymal cells sloughed off of the lateral wall. Our results collectively suggested that RSPH9 is essential for ciliary structure and motility of mouse ependymal cilia, and its deletion causes the pathogenesis of hydrocephalus.

Highlights

  • Hydrocephalus is a brain disorder triggered by cerebrospinal fluid accumulation in brain cavities

  • The directional flow of cerebrospinal fluid (CSF) is driven by continuous CSF secretion and by the orchestrated beating of bundles of motile cilia that are located at the apical surface of ependymal ­cells[7]

  • RSPH9 is known to be a component of the axonemal radial spoke head complex, which is a thin stalk attached to the outer doublet microtubule in motile cilia

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Summary

Introduction

Hydrocephalus is a brain disorder triggered by cerebrospinal fluid accumulation in brain cavities. Even though cerebrospinal fluid flow is known to be driven by the orchestrated beating of the bundled motile cilia of ependymal cells, little is known about the mechanism of ciliary motility. Hydrocephalus in Rsph9−/− mice results in the development of astrogliosis, microgliosis and cerebrovascular abnormalities. Our results collectively suggested that RSPH9 is essential for ciliary structure and motility of mouse ependymal cilia, and its deletion causes the pathogenesis of hydrocephalus. Interaction between radial spoke heads and the central pair of single microtubules is the central for ciliary regulation. Previous studies showed that Chlamydomonas RSP9 mutant strains lack the entire radial spoke head complex and displacement of the central pair of single m­ icrotubules[9]. Our study reveals the role of RSPH9 in hydrocephalus pathogenesis and ependymal cilia motility in the developing mouse brain

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