Pkd2l1 is required for mechanoception in cerebrospinal fluid-contacting neurons and maintenance of spine curvature

Jenna R Sternberg,Andrew E Prendergast,Lucie Brosse,Adeline Orts-Del’Immagine,Claude Boccara,Shusaku Kurisu,Patrick Delmas,Lydia Djenoune,Jonathan R Mcdearmid,Yasmine Cantaut-Belarif,Olivier Thouvenin,Claire Wyart,Laura Castillo,Pierre-Luc Bardet,Hitoshi Okamoto

doi:10.1038/s41467-018-06225-x

Abstract

Defects in cerebrospinal fluid (CSF) flow may contribute to idiopathic scoliosis. However, the mechanisms underlying detection of CSF flow in the central canal of the spinal cord are unknown. Here we demonstrate that CSF flows bidirectionally along the antero-posterior axis in the central canal of zebrafish embryos. In the cfap298tm304 mutant, reduction of cilia motility slows transport posteriorly down the central canal and abolishes spontaneous activity of CSF-contacting neurons (CSF-cNs). Loss of the sensory Pkd2l1 channel nearly abolishes CSF-cN calcium activity and single channel opening. Recording from isolated CSF-cNs in vitro, we show that CSF-cNs are mechanosensory and require Pkd2l1 to respond to pressure. Additionally, adult pkd2l1 mutant zebrafish develop an exaggerated spine curvature, reminiscent of kyphosis in humans. These results indicate that CSF-cNs are mechanosensory cells whose Pkd2l1-driven spontaneous activity reflects CSF flow in vivo. Furthermore, Pkd2l1 in CSF-cNs contributes to maintenance of natural curvature of the spine.

Highlights

Defects in cerebrospinal fluid (CSF) flow may contribute to idiopathic scoliosis
Using population calcium imaging in 24–30 hpf paralyzed wild-type embryos, we found that CSF-contacting neurons (CSF-cNs) located near ventral cilia within the central canal were highly active (Fig. 2d and Supplementary Movie 4)
Measurements of particle trajectories performed on paralyzed zebrafish embryos show complex bidirectional fluid dynamics in the central canal of the spinal cord

Summary

Introduction

Defects in cerebrospinal fluid (CSF) flow may contribute to idiopathic scoliosis. the mechanisms underlying detection of CSF flow in the central canal of the spinal cord are unknown. Adult pkd2l1 mutant zebrafish develop an exaggerated spine curvature, reminiscent of kyphosis in humans These results indicate that CSF-cNs are mechanosensory cells whose Pkd2l1-driven spontaneous activity reflects CSF flow in vivo. Primary candidates for sensory cells to detect changes in CSF flow or content are the CSF-contacting neurons (CSF-cNs) that line the brain ventricles and central canal of the spinal cord. Mouse, and macaque, CSF-cNs express the transient receptor potential channel Pkd2l1 (polycystic kidney disease 2-like 1), known as TRPP317,18. Previous studies showed these cells utilize Pkd2l1 to sense pH changes and respond to bending of the spinal cord during locomotion[19,20,21]. Whether the cells can directly direct mechanical perturbation or sense CSF flow has not been proven

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Conclusion