scholarly journals Mutations in Kinesin Family Member 6 Reveal Specific Role in Ependymal Cell Function and Human Neuro-Cranial Development

2018 ◽  
Author(s):  
Mia J. Konjikusic ◽  
Patra Yeetong ◽  
Rungnapa Ittiwut ◽  
Kanya Suphapeetiporn ◽  
John B. Wallingford ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Intellectual Disability ◽  
Ependymal Cell ◽  
Ventricular System ◽  
Mutant Mice ◽  
Cerebrospinal Fluid Flow ◽  
Cranial Development ◽  
Truncating Mutation ◽  
The Brain ◽  
Kinesin Family

ABSTRACTCerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain, with localized flow being established by the polarized beating of the ependymal cell (EC) cilia. Here, we report a homozygous one base-pair deletion, c.1193delT (p.Leu398Glnfs*2), in the Kinesin Family Member 6 (KIF6) gene in a child displaying neurocranial defects and intellectual disability. To test the pathogenicity of this novel human KIF6 mutation we engineered an analogous C-terminal truncating mutation in mouse. These mutant mice display severe, postnatal-onset hydrocephalus. We generated a Kif6-LacZ transgenic mouse strain and report expression specifically and uniquely within the ependymal cell (EC) layer of the brain, without labeling other multiciliated mouse tissues. Analysis of Kif6 mutant mice with scanning electron microscopy (SEM) and immunofluorescence (IF) revealed a reduction in EC cilia, without effect on other multiciliated tissues. Consistent with our findings in mice, defects of the ventricular system and EC cilia were observed in kif6 mutant zebrafish. Overall, this work describes the first clinically-defined KIF6 homozygous null mutation in human and defines KIF6 as a conserved mediator of neuro-cranial morphogenesis with a specific role in the maintenance of EC cilia in vertebrates.AUTHOR SUMMARYCerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain. Localized flows of cerebrospinal fluid throughout the ventricular system of the brain are established from the polarized beating of the ependymal cell (EC) cilia. Here, we identified a homozygous truncating mutation in KIF6 in a child displaying neuro-cranial defects and intellectual disability. To test the function of KIF6 in vivo, we engineered mutations of Kif6 in mouse. These Kif6 mutant mice display severe hydrocephalus, coupled with a loss of EC cilia. Similarly, we observed hydrocephalus and a reduction in EC cilia in kif6 mutant zebrafish. Overall, this work describes the first clinically-defined KIF6 mutation in human, while our animal studies demonstrate the pathogenicity of mutations in KIF6 and establish KIF6 as a conserved mediator of neuro-cranial development and EC cilia maintenance in vertebrates.

Spatially Organized Ciliary Beating Compartmentalizes Cerebrospinal Fluid Flow in the Brain and Regulates Ventricular Development

2018 ◽  
Author(s):  
Emilie W. Olstad ◽  
Christa Ringers ◽  
Adinda Wens ◽  
Jan N. Hansen ◽  
Cecilia Brandt ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Fluid Flow ◽  
Cerebrospinal Fluid Flow ◽  
Ciliary Beating ◽  
The Brain

scholarly journals Shear-Induced Amyloid Aggregation in the Brain: V. Are Alzheimer’s and Other Amyloid Diseases Initiated in the Lower Brain and Brainstem by Cerebrospinal Fluid Flow Stresses?

2020 ◽  
pp. 1-24
Author(s):  
Conrad N. Trumbore
Keyword(s):  
Cerebrospinal Fluid ◽  
Conformational Changes ◽  
Extensional Flow ◽  
Amyloid Β ◽  
High Energy ◽  
Mechanical Agitation ◽  
Cerebrospinal Fluid Flow ◽  
Pulse Waves ◽  
Amyloid Diseases ◽  
The Brain

Amyloid-β (Aβ) and tau oligomers have been identified as neurotoxic agents responsible for causing Alzheimer’s disease (AD). Clinical trials using Aβ and tau as targets have failed, giving rise to calls for new research approaches to combat AD. This paper provides such an approach. Most basic AD research has involved quiescent Aβ and tau solutions. However, studies involving laminar and extensional flow of proteins have demonstrated that mechanical agitation of proteins induces or accelerates protein aggregation. Recent MRI brain studies have revealed high energy, chaotic motion of cerebrospinal fluid (CSF) in lower brain and brainstem regions. These and studies showing CSF flow within the brain have shown that there are two energetic hot spots. These are within the third and fourth brain ventricles and in the neighborhood of the circle of Willis blood vessel region. These two regions are also the same locations as those of the earliest Aβ and tau AD pathology. In this paper, it is proposed that cardiac systolic pulse waves that emanate from the major brain arteries in the lower brain and brainstem regions and whose pulse waves drive CSF flows within the brain are responsible for initiating AD and possibly other amyloid diseases. It is further proposed that the triggering of these diseases comes about because of the strengthening of systolic pulses due to major artery hardening that generates intense CSF extensional flow stress. Such stress provides the activation energy needed to induce conformational changes of both Aβ and tau within the lower brain and brainstem region, producing unique neurotoxic oligomer molecule conformations that induce AD.

scholarly journals Ciliary Beating Compartmentalizes Cerebrospinal Fluid Flow in the Brain and Regulates Ventricular Development

2019 ◽  
Vol 29 (2) ◽  
pp. 229-241.e6 ◽  
Author(s):  
Emilie W. Olstad ◽  
Christa Ringers ◽  
Jan N. Hansen ◽  
Adinda Wens ◽  
Cecilia Brandt ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Fluid Flow ◽  
Cerebrospinal Fluid Flow ◽  
Ciliary Beating ◽  
The Brain

Impermeability of the Blood—Cerebrospinal Fluid Barrier for Angiotensin II in Rats

1976 ◽  
Vol 51 (s3) ◽  
pp. 399s-402s ◽  
Author(s):  
P. Schelling ◽  
J. S. Hutchinson ◽  
U. Ganten ◽  
G. Sponer ◽  
D. Ganten
Keyword(s):  
Cerebrospinal Fluid ◽  
Angiotensin Ii ◽  
Intravenous Infusion ◽  
Ventricular System ◽  
Cisterna Magna ◽  
Biochemical Methods ◽  
Intravenous Infusions ◽  
Artificial Cerebrospinal Fluid ◽  
Brain Ventricular System ◽  
The Brain

1. Anaesthetized, nephrectomized rats were infused intravenously with unlabelled angiotensin II (AII) or with [3H]angiotensin II (3H-labelled AII). The brain ventricular system was perfused with artificial cerebrospinal fluid. The perfusate was collected from the cisterna magna and analysed for AII by radioimmunological and biochemical methods. 2. No increase of immunoreactive AII in cerebrospinal fluid could be shown during intravenous infusion of AII. 3. During intravenous infusions of 3H-labelled AII at pressor doses small amounts of radioactivity were found in cerebrospinal fluid perfusate. 4. The radioactivity of cerebrospinal fluid outflow could not be related to AII.

scholarly journals A novel hypomorphic allele of Spag17 causes primary ciliary dyskinesia phenotypes in mice

2020 ◽  
Vol 13 (10) ◽  
pp. dmm045344
Author(s):  
Zakia Abdelhamed ◽  
Marshall Lukacs ◽  
Sandra Cindric ◽  
Heymut Omran ◽  
Rolf W. Stottmann
Keyword(s):  
Cerebrospinal Fluid ◽  
Fluid Flow ◽  
Primary Ciliary Dyskinesia ◽  
Human Condition ◽  
Central Pair ◽  
Cerebrospinal Fluid Flow ◽  
Hypomorphic Allele ◽  
Motile Cilia ◽  
The Brain ◽  
Ciliary Dyskinesia

ABSTRACTPrimary ciliary dyskinesia (PCD) is a human condition of dysfunctional motile cilia characterized by recurrent lung infection, infertility, organ laterality defects and partially penetrant hydrocephalus. We recovered a mouse mutant from a forward genetic screen that developed many of the hallmark phenotypes of PCD. Whole-exome sequencing identified this primary ciliary dyskinesia only (Pcdo) allele to be a nonsense mutation (c.5236A>T) in the Spag17 coding sequence creating a premature stop codon (K1746*). The Pcdo variant abolished several isoforms of SPAG17 in the Pcdo mutant testis but not in the brain. Our data indicate differential requirements for SPAG17 in different types of motile cilia. SPAG17 is essential for proper development of the sperm flagellum and is required for either development or stability of the C1 microtubule structure within the central pair apparatus of the respiratory motile cilia, but not the brain ependymal cilia. We identified changes in ependymal ciliary beating frequency, but these did not appear to alter lateral ventricle cerebrospinal fluid flow. Aqueductal stenosis resulted in significantly slower and abnormally directed cerebrospinal fluid flow, and we suggest that this is the root cause of the hydrocephalus. The Spag17Pcdo homozygous mutant mice are generally viable to adulthood but have a significantly shortened lifespan, with chronic morbidity. Our data indicate that the c.5236A>T Pcdo variant is a hypomorphic allele of Spag17 that causes phenotypes related to motile, but not primary, cilia. Spag17Pcdo is a useful new model for elucidating the molecular mechanisms underlying central pair PCD pathogenesis in the mouse.This article has an associated First Person interview with the first author of the paper.

Insight into the patterns of cerebrospinal fluid flow in the human ventricular system using MR velocity mapping

NeuroImage ◽  
2010 ◽  
Vol 51 (1) ◽  
pp. 42-52 ◽  
Author(s):  
Andreas Stadlbauer ◽  
Erich Salomonowitz ◽  
Wilma van der Riet ◽  
Michael Buchfelder ◽  
Oliver Ganslandt
Keyword(s):  
Cerebrospinal Fluid ◽  
Fluid Flow ◽  
Ventricular System ◽  
Velocity Mapping ◽  
Cerebrospinal Fluid Flow ◽  
Insight Into

Exchange of calcium between blood, brain, and cerebrospinal fluid

1965 ◽  
Vol 208 (6) ◽  
pp. 1058-1064 ◽  
Author(s):  
Leonard Graziani ◽  
Anthony Escriva ◽  
Robert Katzman
Keyword(s):  
Cerebrospinal Fluid ◽  
Steady State ◽  
Brain Tissue ◽  
Specific Activity ◽  
Ventricular System ◽  
Passive Diffusion ◽  
Bulk Fluid ◽  
Fluid Formation ◽  
The Brain ◽  
Rate Of Movement

Ca exchange was measured in anesthetized cats during steady-state ventriculocisternal perfusions. When Ca45 was added to the perfusate the efflux coefficient from CSF averaged 0.025 ml/min of CSF cleared of Ca45. This coefficient was independent of CSF Ca concentration, indicating passive diffusion. About onethird of this isotope was recovered in brain tissue, two-thirds presumably diffused into blood. The brain radioactivity was localized to areas immediately adjacent to the CSF pathway. When the isotope was given systemically, the efflux coefficient into the ventricular system averaged 0.015 ml/min of serum effectively cleared of Ca45. In these experiments the specific activity of the CSF approached that of the serum. At the same time the specific activity of the brain Ca was low. Hence, the chief source of the Ca entering CSF must be blood. The rate of movement of Ca45 from blood to CSF was not altered when CSF formation was suppressed by adding acetazolamide or lowering the pH of the perfusate. This suggests that Ca transport is independent of the bulk fluid formation.

Three-dimensional cerebrospinal fluid flow within the human ventricular system

2008 ◽  
Vol 11 (2) ◽  
pp. 123-133 ◽  
Author(s):  
L. Howden ◽  
D. Giddings ◽  
H. Power ◽  
A. Aroussi ◽  
M. Vloeberghs ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Fluid Flow ◽  
Three Dimensional ◽  
Ventricular System ◽  
Cerebrospinal Fluid Flow

Spontaneous rupture of a metastatic brain tumor into the ventricular system

1971 ◽  
Vol 34 (3) ◽  
pp. 412-416
Author(s):  
Robert H. Wilkins ◽  
Wang-Kuen Wu
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Tumor ◽  
Spontaneous Rupture ◽  
Ventricular System ◽  
Metastatic Brain Tumor ◽  
Content Type ◽  
Surgical Exposure ◽  
First Case ◽  
The Brain ◽  
Fine Print

✓ Two cases are reported in which spontaneous rupture of a metastatic brain tumor occurred into the ventricular system, leading to the dissemination of the tumor contents in the cerebrospinal fluid. The site of rupture was demonstrated by ventriculography in the first case and by surgical exposure in the second. These cases support the assumption that metastatic neoplasms within the brain may rupture into the ventricular system and spread via the cerebrospinal fluid pathways.

scholarly journals Congenital Hydrocephalic Monster in an Indigenous Gir Calf: A Case Report

2020 ◽  
Vol 16 (01) ◽  
pp. 69-70
Author(s):  
DN Borakhatariya ◽  
Rupesh J Raval ◽  
Karsan B Vala ◽  
Bakti P Chavda ◽  
Sanny G Prajapati
Keyword(s):  
Cerebrospinal Fluid ◽  
Case Report ◽  
Virus Infection ◽  
Subarachnoid Space ◽  
Bluetongue Virus ◽  
Autosomal Recessive ◽  
Recessive Gene ◽  
Ventricular System ◽  
Present Case Report ◽  
The Brain

There are several types of fetal dropsy (fetal ascites, fetal anasarca, fetal hydrocephalus), which have obstetrical importance preventing normal easy delivery of calf. Hydrocephalus is one of the fetal causes of dystocia. It is characterized by an accumulation of fluid which may be in the ventricular system or between the brain and the subarachnoid space. The swelling or enlargement of cranium occurs as a result of an imbalance between formation and drainage of cerebrospinal fluid (Arthur et al., 2001). This congenital dropsical condition is associated with an autosomal recessive gene, whereas some cases are due to BVD-MD or bluetongue virus infection in bovine (Roberts, 1986). Though this dropsical condition is rare in Gir cattle, it is reported in many other species (Dhami et al., 2007; Kumar et al., 2010; Parmar et al., 2018). The present case report depicts an unusual instance of hydrocephalic monster in an indigenous Gir calf, causing dystocia, which was successfully managed by per vaginum.

Sign in / Sign up

Export Citation Format

Share Document