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Scheme of the anatomy of the ventral part of the third ventricle (v3V). The lateral ventricles (lV), the dorsal part of the third ventricle (d3V) and the fourth ventricle (4V) contain a choroid plexus (CP) that secretes CSF. Propelled by beating cilia bundles located at the apical side of ependymal cells, CSF partitions above the ependymal cell layer in a complex manner (figure 3a). Subependymal neurons may be scattered or form clusters (nuclei) that carry out specific functions such as control of circadian timing or control of energy metabolism. In the v3v, the ependymal layer contains tanycytes, which are specialized glia cells that are biciliated and send long processes that contact neurons, glia and blood vessels in the subependymal brain tissue. Some of the tanycytes have stem cell properties. CSF and interstitial fluid can pass between ependymal cells, while tanycytes have occluding junctions that form a seal preventing passage of solutes and water.
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The brain ventricles are interconnected, elaborate cavities that traverse the brain. They are filled with cerebrospinal fluid (CSF) that is, to a large part, produced by the choroid plexus, a secretory epithelium that reaches into the ventricles. CSF is rich in cytokines, growth factors and extracellular vesicles that glide along the walls of ventr...
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Context 1
... ventricles co-develop with the nervous system so that around the time of birth, four distinct brain ventricles have formed. In the postnatal brain, ventricles are enclosed by the ependyma that consists mostly of E1 cells (ependymal cells, ependymocytes, figure 1; [5,6]). E1 cells derive from embryonic radial glia cells [7,8] and carry a characteristic apical bundle of motile cilia that coordinately beat and in this way propel CSF along the ventricular wall (figure 1). ...
Context 2
... E1 cells, E2 and E3 cells have their apical side directly exposed to CSF. Basally, tanycytes extend one or two long processes that reach deep into the brain parenchyma ( figure 1; [51,53]) where they contact several hypothalamic nuclei as well as blood vessels. ...
Context 3
... ventricles co-develop with the nervous system so that around the time of birth, four distinct brain ventricles have formed. In the postnatal brain, ventricles are enclosed by the ependyma that consists mostly of E1 cells (ependymal cells, ependymocytes, figure 1; [5,6]). E1 cells derive from embryonic radial glia cells [7,8] and carry a characteristic apical bundle of motile cilia that coordinately beat and in this way propel CSF along the ventricular wall (figure 1). ...
Citations
... Interestingly, the proband also has intercranial hypertension. The CSF inside the brain ventricles moves by synchronized activity of cilia, and the ciliary pattern formation as well as the directional flow of the fluid is regulated by PCP (58)(59)(60)(61)(62). Hence, improper beating of the cilia due to abnormal PCP may cause this hypertension. ...
Nascent proteins destined for the cell membrane and the secretory pathway are targeted to the endoplasmic reticulum (ER) either posttranslationally or cotranslationally. The signal-independent pathway, containing the protein TMEM208, is one of three pathways that facilitates the translocation of nascent proteins into the ER. The in vivo function of this protein is ill characterized in multicellular organisms. Here, we generated a CRISPR-induced null allele of the fruit fly ortholog CG8320/Tmem208 by replacing the gene with the Kozak-GAL4 sequence. We show that Tmem208 is broadly expressed in flies and that its loss causes lethality, although a few short-lived flies eclose. These animals exhibit wing and eye developmental defects consistent with impaired cell polarity and display mild ER stress. Tmem208 physically interacts with Frizzled (Fz), a planar cell polarity (PCP) receptor, and is required to maintain proper levels of Fz. Moreover, we identified a child with compound heterozygous variants in TMEM208 who presents with developmental delay, skeletal abnormalities, multiple hair whorls, cardiac, and neurological issues, symptoms that are associated with PCP defects in mice and humans. Additionally, fibroblasts of the proband display mild ER stress. Expression of the reference human TMEM208 in flies fully rescues the loss of Tmem208 , and the two proband-specific variants fail to rescue, suggesting that they are loss-of-function alleles. In summary, our study uncovers a role of TMEM208 in development, shedding light on its significance in ER homeostasis and cell polarity.
... Since cilia mainly contribute to the near-wall and not the bulk CSF flow, one could predict that cilia will have less impact when ventricles are big, such as in humans, and thereby a minor causal role in hydrocephalus. Nevertheless, motile cilia will generate a directional fluid flow at the surface of the ventricle and as such have been suggested to contribute to the establishment of signaling molecule gradients within the brain (23,24). This was experimentally shown by one study so far, which has observed abnormal neuronal migration during postnatal brain development in a cilia mutant animal (13). ...
The brain uses a specialized system to transport cerebrospinal fluid (CSF). This system consists of interconnected ventricles lined by ependymal cells, which generate a directional flow upon beating of their motile cilia. Motile cilia act jointly with other physiological factors, including active CSF secretion and cardiac pressure gradients, to regulate CSF dynamics. The content and movement of CSF are thought to be important for brain physiology. Yet, the link between cilia-mediated CSF flow and brain function is poorly understood. In this study, we addressed the role of motile cilia-mediated CSF flow on brain development and physiology using zebrafish larvae as a model system. By analyzing mutant animals with paralyzed cilia, we identified that loss of ciliary motility did not alter progenitor proliferation, overall brain morphology, or spontaneous neural activity. Instead, we identified that cilia paralysis led to randomization of brain asymmetry. We also observed altered neuronal responses to photic stimulation, especially in the optic tectum and hindbrain. Since astroglia contact CSF at the ventricular walls and are essential for regulating neuronal activity, we next investigated astroglial activity in motile cilia mutants. Our analyses revealed a striking reduction in astroglial calcium signals both during spontaneous and light-evoked activity. Altogether, our findings highlight a novel role of motile cilia-mediated flow in regulating brain physiology through modulation of neural and astroglial networks.
... These cells are also affected by seasonality changes (Dardente H and Migaud M., 2021). Recent studies have shown that cilia, coating some of the cells lining the wall of the 3 rd ventricle drive CSF flow and might have significant effects on the directional CSF flow in the adjacent hypothalamus parenchyma (Eichele et al., 2020). In particular, cilia-driven streams of signaling molecules offer an interesting perspective to understand better the underpinnings of CSF-borne signals dynamically transmitted to the brain. ...
... CPe epithelial cells develop 9 + 0 cilia patches that exhibit transient motility during the neonatal period [152,153]. In adulthood, neural stem cells in the subventricular zone extend a solitary 9 + 0 non-motile cilium into the CSF [124,154]. During the workshop, discussion centered on the 9 + 2 ependymal motile cilia that grow in tufts on the apical surface of mature ependymal cells that line the ventricles, as mounting evidence supports their involvement in PHH of prematurity pathophysiology. ...
The Hydrocephalus Association (HA) workshop, Driving Common Pathways: Extending Insights from Posthemorrhagic Hydrocephalus, was held on November 4 and 5, 2019 at Washington University in St. Louis. The workshop brought together a diverse group of basic, translational, and clinical scientists conducting research on multiple hydrocephalus etiologies with select outside researchers. The main goals of the workshop were to explore areas of potential overlap between hydrocephalus etiologies and identify drug targets that could positively impact various forms of hydrocephalus. This report details the major themes of the workshop and the research presented on three cell types that are targets for new hydrocephalus interventions: choroid plexus epithelial cells, ventricular ependymal cells, and immune cells (macrophages and microglia).
... Even with the possibility of cytosolic proteins released from the broken ventricular area or dying neuroepithelial cells, the CSF proteome of mouse embryos could be affected by the proliferative condition of the mouse embryonic neuroepithelium and the secretory status of the choroid plexus. The secretion of extracellular vesicles and secretory proteins from both neuroepithelium and the choroid plexus could be regulated from signaling pathways downstream of the cilium [74][75][76]. We figured that signaling through the primary cilia could be regulated from CSF factors. ...
The developmental functions of primary cilia and the downstream signaling pathways have been widely studied; however, the roles of primary cilia in the developing neurovascular system are not clearly understood. In this study, we found that ablation of genes encoding ciliary transport proteins such as intraflagellar transport homolog 88 (Ift88) and kinesin family member 3a (Kif3a) in cortical radial progenitors led to periventricular heterotopia during late mouse embryogenesis. Conditional mutation of primary cilia unexpectedly caused breakdown of both the neuroepithelial lining and the blood‐choroid plexus barrier. Choroidal leakage was partially caused by enlargement of the choroid plexus in the cilia mutants. We found that the choroid plexus expressed platelet‐derived growth factor A (Pdgf‐A) and that Pdgf‐A expression was ectopically increased in cilia‐mutant embryos. Cortices obtained from embryos in utero electroporated with Pdgfa mimicked periventricular heterotopic nodules of the cilia mutant. These results suggest that defective ciliogenesis in both cortical progenitors and the choroid plexus leads to breakdown of cortical and choroidal barriers causing forebrain neuronal dysplasia, which may be related to developmental cortical malformation. Forebrain heterotopia development caused by combined barrier breakdown.
... ΕVs in the CNS The brain is a complex structure that consists of diverse groups of neurons and glial cells, which synchronize their activity through extensive interactions integrated into neural networks [53]. EVs can be produced and released by CNS cells, including neurons, astrocytes, oligodendrocytes and microglia as well as neural progenitor cells, and can reach the cerebrospinal fluid (CSF) [53,[111][112][113]. ...
Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that contain various biomolecules, including nucleic acids, proteins, and lipids, and are manufactured and released by virtually all cell types. There is evidence that EVs are involved in intercellular communication, acting in an autocrine, paracrine, or/and endocrine manner. EVs are released by the cells of the central nervous system (CNS), including neurons, astrocytes, oligodendrocytes and microglia, and have the ability to cross the blood brain barrier (BBB) and enter the systemic circulation. Neuroendocrine cells are specialized neurons that secrete hormones directly into blood vessels, such as the hypophyseal portal system or the systemic circulation, a process that allows neuroendocrine integration to take place. In mammals, neuroendocrine cells are widely distributed throughout various anatomic compartments, with the hypothalamus being a central neuroendocrine integrator. The hypothalamus is a key part of the Stress System (SS), a highly conserved neuronal/neuroendocrine system aiming at maintaining systemic homeostasis, when the latter is threatened by various stressors. The central parts of the SS are the interconnected hypothalamic Corticotropin-releasing Hormone (CRH) and the brainstem Locus Caeruleus-Norepinephrine (LC-NE) systems, while their peripheral parts are respectively the pituitary-adrenal axis, and the sympathetic nervous/sympatho-adrenomedullary systems (SNS-SAM) as well as components of the parasympathetic system (PNS). During stress, multiple CNS loci show plasticity and undergo remodeling, partly mediated by increased glutamatergic and noradrenergic activity, and actions of cytokines and glucocorticoids (GCs), all regulated by the interaction of the hypothalamic-pituitary-adrenal (HPA) axis and the LC-NE/SNS-SAM systems. In addition, there are peripheral changes due to the increased secretion of stress hormones and pro-inflammatory cytokines in the context of stress-related systemic (para)inflammation.
... The flow is mainly generated due to the interactions between the cilia and fluid particles in the flow domain. In the literature, there are several studies monitoring CSF movements in zebrafish embryos employing photoactivatable proteins or particles to determine CSF flow patterns [8,37,68,70,71]. These flow measurements aim to demystify the CSF fluid properties in embryonic zebrafish brain [72] and depend on in vivo investigations paired with advanced imaging techniques, such as optical coherence tomography [8,37]. ...
Motile cilia are hair-like microscopic structures which generate directional flow to provide fluid transport in various biological processes. Ciliary beating is one of the sources of cerebrospinal flow (CSF) in brain ventricles. In this study, we investigated how the tilt angle, quantity, and phase relationship of cilia affect CSF flow patterns in the brain ventricles of zebrafish embryos. For this purpose, two-dimensional computational fluid dynamics (CFD) simulations are performed to determine the flow fields generated by the motile cilia. The cilia are modeled as thin membranes with prescribed motions. The cilia motions were obtained from a two-day post-fertilization zebrafish embryo previously imaged via light sheet fluorescence microscopy. We observed that the cilium angle significantly alters the generated flow velocity and mass flow rates. As the cilium angle gets closer to the wall, higher flow velocities are observed. Phase difference between two adjacent beating cilia also affects the flow field as the cilia with no phase difference produce significantly lower mass flow rates. In conclusion, our simulations revealed that the most efficient method for cilia-driven fluid transport relies on the alignment of multiple cilia beating with a phase difference, which is also observed in vivo in the developing zebrafish brain.
... Fluid transport in confined environments through metachronal coordination is ubiquitous in biological systems (8,34,35). The deformability and stretchability of our soft-robotic ciliated epidermis and the decoupling between the actuation input and the surface morphology enable us to deploy it in tubular structures for fluid transportation. ...
The fluid manipulation capabilities of current artificial cilia are severely handicapped by the inability to reconfigure near-surface flow on various static or dynamically deforming three-dimensional (3D) substrates. To overcome this challenge, we propose an electrically driven soft-robotic ciliated epidermis with multiple independently controlled polypyrrole bending actuators. The beating kinematics and the coordination of multiple actuators can be dynamically reconfigured to control the strength and direction of fluid transportation. We achieve fluid transportation along and perpendicular to the beating directions of the actuator arrays, and toward or away from the substrate. The ciliated epidermises are bendable and stretchable and can be deployed on various static or dynamically deforming 3D surfaces. They enable previously difficult to obtain fluid manipulation functionalities, such as transporting fluid in tubular structures or enhancing fluid transportation near dynamically bending and expanding surfaces.
... There is a net flow from the ventricles to the Cisterna magna. From there, the CSF flow divides into the cerebral convexities and the spinal canal [12,[30][31][32][33]. The coordinated action of the cilia of the plexus ependyma maintains a network of fluid flows in the 3rd ventricle of the mouse, which allows precise CSF transport. ...
... The coordinated action of the cilia of the plexus ependyma maintains a network of fluid flows in the 3rd ventricle of the mouse, which allows precise CSF transport. A cilia-based switch can periodically alter the CSF flow pattern which may control distribution of endogenous and exogenous compounds in the 3rd ventricle [33,34]. Complex flow patterns were also present in the third ventricles of rats and pigs [33], suggesting that ciliated epithelia can generate and maintain complex, spatiotemporally regulated flow networks. ...
... A cilia-based switch can periodically alter the CSF flow pattern which may control distribution of endogenous and exogenous compounds in the 3rd ventricle [33,34]. Complex flow patterns were also present in the third ventricles of rats and pigs [33], suggesting that ciliated epithelia can generate and maintain complex, spatiotemporally regulated flow networks. ...
The cerebrospinal fluid (CSF) space is convoluted. CSF flow oscillates with a net flow from the ventricles towards the cerebral and spinal subarachnoid space. This flow is influenced by heartbeats, breath, head or body movements as well as the activity of the ciliated epithelium of the plexus and ventricular ependyma. The shape of the CSF space and the CSF flow preclude rapid equilibration of cells, proteins and smaller compounds between the different parts of the compartment. In this review including reinterpretation of previously published data we illustrate, how anatomical and (patho)physiological conditions can influence routine CSF analysis. Equilibration of the components of the CSF depends on the size of the molecule or particle, e.g., lactate is distributed in the CSF more homogeneously than proteins or cells. The concentrations of blood-derived compounds usually increase from the ventricles to the lumbar CSF space, whereas the concentrations of brain-derived compounds usually decrease. Under special conditions, in particular when distribution is impaired, the rostro-caudal gradient of blood-derived compounds can be reversed. In the last century, several researchers attempted to define typical CSF findings for the diagnosis of several inflammatory diseases based on routine parameters. Because of the high spatial and temporal variations, findings considered typical of certain CNS diseases often are absent in parts of or even in the entire CSF compartment. In CNS infections, identification of the pathogen by culture, antigen detection or molecular methods is essential for diagnosis.
... The aqueduct in rats is oriented in a horizontal position combining a valve and guiding system equipped with a central wire, the Reissner fiber, consisting of spondin fibrils that connect the roof of the third ventricle with the sacral tip of the spinal canal (Muñoz et al., 2019;Woollam & Collins, 2005). Moreover, CSF flow in rats is dependent on CSF movements induced by motile cilia, which create a steady fluid movement above the ventricular ependyma and choroid plexus in correspondence to body movements and passive propagation of CSF (Eichele et al., 2019;Olstad et al., 2019;Wan & Jékely, 2019). ...
... In humans, there are several genetic aberrations associated with HC, such as Kartagener syndrome (Fliegauf et al., 2007) and flagellar disorders (Morimoto et al., 2019), but it seems that humans are less dependent than rodents on ciliary motility for the propulsion of CSF. Nevertheless, ciliary pathology might be involved in a failure of physiological flow sensing and signal transduction (Eichele et al., 2019). Knowledge from animal-based HC studies might therefore be restricted and should be transferred to human physiology with caution. ...
With the advent of real-time MRI, the motion and passage of cerebrospinal fluid can be visualized without gating and exclusion of low-frequency waves. This imaging modality gives insights into low-volume, rapidly oscillating cardiac-driven movement as well as sustained, high-volume, slowly oscillating inspiration-driven movement. Inspiration means a spontaneous or artificial increase in the intrathoracic dimensions independent of body position. Alterations in thoracic diameter enable the thoracic and spinal epidural venous compartments to be emptied and filled, producing an upward surge of cerebrospinal fluid inside the spine during inspiration; this surge counterbalances the downward pooling of venous blood toward the heart. Real-time MRI, as a macroscale in vivo observation method, could expand our knowledge of neurofluid dynamics, including how astrocytic fluid preloading is adjusted and how brain buoyancy and turgor are maintained in different postures and zero gravity. Along with these macroscale findings, new microscale insights into aquaporin-mediated fluid transfer, its sensing by cilia, and its tuning by nitric oxide will be reviewed. By incorporating clinical knowledge spanning several disciplines, certain disorders—congenital hydrocephalus with Chiari malformation, idiopathic intracranial hypertension, and adult idiopathic hydrocephalus—are interpreted and reviewed according to current concepts, from the basics of the interrelated systems to their pathology.
