A H Dur1,2, T Tang3, S Viviano1,4, A Sekuri2, H R Willsey5, H D Tagare3, K T Kahle1,6, E Deniz7,8. 1. Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. 2. Acibadem Mehmet Ali Aydinlar University School of Medicine, Istanbul, Turkey. 3. Department of Radiology and Biomedical Imaging, Yale University, 300 Cedar St, New Haven, CT, 06510, USA. 4. Pediatric Genomics Discovery Program, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. 5. Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, 94143, USA. 6. Department of Neurosurgery and Cellular & Molecular Physiology, and Centers for Mendelian Genomics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. 7. Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. engin.deniz@yale.edu. 8. Pediatric Genomics Discovery Program, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. engin.deniz@yale.edu.
Abstract
BACKGROUND: Hydrocephalus, the pathological expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles, is a common, deadly disease. In the adult, cardiac and respiratory forces are the main drivers of CSF flow within the brain ventricular system to remove waste and deliver nutrients. In contrast, the mechanics and functions of CSF circulation in the embryonic brain are poorly understood. This is primarily due to the lack of model systems and imaging technology to study these early time points. Here, we studied embryos of the vertebrate Xenopus with optical coherence tomography (OCT) imaging to investigate in vivo ventricular and neural development during the onset of CSF circulation. METHODS: Optical coherence tomography (OCT), a cross-sectional imaging modality, was used to study developing Xenopus tadpole brains and to dynamically detect in vivo ventricular morphology and CSF circulation in real-time, at micrometer resolution. The effects of immobilizing cilia and cardiac ablation were investigated. RESULTS: In Xenopus, using OCT imaging, we demonstrated that ventriculogenesis can be tracked throughout development until the beginning of metamorphosis. We found that during Xenopus embryogenesis, initially, CSF fills the primitive ventricular space and remains static, followed by the initiation of the cilia driven CSF circulation where ependymal cilia create a polarized CSF flow. No pulsatile flow was detected throughout these tailbud and early tadpole stages. As development progressed, despite the emergence of the choroid plexus in Xenopus, cardiac forces did not contribute to the CSF circulation, and ciliary flow remained the driver of the intercompartmental bidirectional flow as well as the near-wall flow. We finally showed that cilia driven flow is crucial for proper rostral development and regulated the spatial neural cell organization. CONCLUSIONS: Our data support a paradigm in which Xenopus embryonic ventriculogenesis and rostral brain development are critically dependent on ependymal cilia-driven CSF flow currents that are generated independently of cardiac pulsatile forces. Our work suggests that the Xenopus ventricular system forms a complex cilia-driven CSF flow network which regulates neural cell organization. This work will redirect efforts to understand the molecular regulators of embryonic CSF flow by focusing attention on motile cilia rather than other forces relevant only to the adult.
BACKGROUND:Hydrocephalus, the pathological expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles, is a common, deadly disease. In the adult, cardiac and respiratory forces are the main drivers of CSF flow within the brain ventricular system to remove waste and deliver nutrients. In contrast, the mechanics and functions of CSF circulation in the embryonic brain are poorly understood. This is primarily due to the lack of model systems and imaging technology to study these early time points. Here, we studied embryos of the vertebrate Xenopus with optical coherence tomography (OCT) imaging to investigate in vivo ventricular and neural development during the onset of CSF circulation. METHODS: Optical coherence tomography (OCT), a cross-sectional imaging modality, was used to study developing Xenopus tadpole brains and to dynamically detect in vivo ventricular morphology and CSF circulation in real-time, at micrometer resolution. The effects of immobilizing cilia and cardiac ablation were investigated. RESULTS: In Xenopus, using OCT imaging, we demonstrated that ventriculogenesis can be tracked throughout development until the beginning of metamorphosis. We found that during Xenopus embryogenesis, initially, CSF fills the primitive ventricular space and remains static, followed by the initiation of the cilia driven CSF circulation where ependymal cilia create a polarized CSF flow. No pulsatile flow was detected throughout these tailbud and early tadpole stages. As development progressed, despite the emergence of the choroid plexus in Xenopus, cardiac forces did not contribute to the CSF circulation, and ciliary flow remained the driver of the intercompartmental bidirectional flow as well as the near-wall flow. We finally showed that cilia driven flow is crucial for proper rostral development and regulated the spatial neural cell organization. CONCLUSIONS: Our data support a paradigm in which Xenopusembryonic ventriculogenesis and rostral brain development are critically dependent on ependymal cilia-driven CSF flow currents that are generated independently of cardiac pulsatile forces. Our work suggests that the Xenopus ventricular system forms a complex cilia-driven CSF flow network which regulates neural cell organization. This work will redirect efforts to understand the molecular regulators of embryonic CSF flow by focusing attention on motile cilia rather than other forces relevant only to the adult.
Authors: Kevin F Chau; Mark W Springel; Kevin G Broadbelt; Hye-Yeon Park; Salih Topal; Melody P Lun; Hillary Mullan; Thomas Maynard; Hanno Steen; Anthony S LaMantia; Maria K Lehtinen Journal: Dev Cell Date: 2015-12-21 Impact factor: 12.270
Authors: Maria K Lehtinen; Mauro W Zappaterra; Xi Chen; Yawei J Yang; Anthony D Hill; Melody Lun; Thomas Maynard; Dilenny Gonzalez; Seonhee Kim; Ping Ye; A Joseph D'Ercole; Eric T Wong; Anthony S LaMantia; Christopher A Walsh Journal: Neuron Date: 2011-03-10 Impact factor: 17.173
Authors: Jonathan T Ting; Brian Kalmbach; Peter Chong; Rebecca de Frates; C Dirk Keene; Ryder P Gwinn; Charles Cobbs; Andrew L Ko; Jeffrey G Ojemann; Richard G Ellenbogen; Christof Koch; Ed Lein Journal: Sci Rep Date: 2018-05-30 Impact factor: 4.996
Authors: Niklas Schwarz; Ulrike B S Hedrich; Hannah Schwarz; Harshad P A; Nele Dammeier; Eva Auffenberg; Francesco Bedogni; Jürgen B Honegger; Holger Lerche; Thomas V Wuttke; Henner Koch Journal: Sci Rep Date: 2017-09-25 Impact factor: 4.379
Authors: María Del Mar Fernández-Arjona; Ana León-Rodríguez; María Dolores López-Ávalos; Jesús M Grondona Journal: Fluids Barriers CNS Date: 2021-03-23