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.

中文翻译：

---

在爪蟾室管膜纤毛中，独立于心脏搏动力驱动胚胎脑脊液循环和大脑发育


背景 脑积水是充满脑脊液 (CSF) 的脑室的病理性扩张，是一种常见的致命疾病。在成人中，心脏和呼吸力是脑室系统内脑脊液流动的主要驱动力，以清除废物和输送营养。相比之下，人们对胚胎大脑中脑脊液循环的机制和功能知之甚少。这主要是由于缺乏模型系统和成像技术来研究这些早期时间点。在这里，我们利用光学相干断层扫描（OCT）成像研究了脊椎动物非洲爪蟾的胚胎，以研究脑脊液循环开始期间的体内心室和神经发育。方法 使用光学相干断层扫描（OCT）（一种横截面成像方式）来研究发育中的非洲爪蟾蝌蚪大脑，并以微米分辨率实时动态检测体内脑室形态和脑脊液循环。研究了固定纤毛和心脏消融的效果。结果在非洲爪蟾中，使用 OCT 成像，我们证明可以在整个发育过程中追踪脑室发生直至变态开始。我们发现，在非洲爪蟾胚胎发生过程中，最初，脑脊液填充原始心室空间并保持静态，随后启动纤毛驱动的脑脊液循环，其中室管膜纤毛产生极化脑脊液流。在整个尾芽和早期蝌蚪阶段没有检测到脉动流。随着发育的进展，尽管非洲爪蟾出现了脉络丛，但心脏力量对脑脊液循环没有贡献，纤毛流仍然是室间双向流和近壁流的驱动力。 我们最终表明，纤毛驱动的流动对于吻端的正常发育和调节空间神经细胞组织至关重要。结论我们的数据支持这样一种范式，其中非洲爪蟾胚胎脑室发生和头侧脑发育严重依赖于室管膜纤毛驱动的脑脊液流，这些流是独立于心脏搏动力产生的。我们的工作表明，非洲爪蟾心室系统形成了一个复杂的纤毛驱动的脑脊液流动网络，可调节神经细胞组织。这项工作将通过关注运动纤毛而不是其他仅与成人相关的力量来重新了解胚胎脑脊液流动的分子调节因子。