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.

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

2020 ◽  
Author(s):  
Zakia Abdelhamed ◽  
Marshall Lukacs ◽  
Sandra Cindric ◽  
Heymut Omran ◽  
Rolf W. Stottmann
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Molecular Mechanisms ◽  
Premature Stop Codon ◽  
Human Condition ◽  
Csf Flow ◽  
Hypomorphic Allele ◽  
Ependymal Cilia ◽  
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 all the 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 at position 1746 (K1746*). The Pcdo variant abolished different isoforms of SPAG17 in the Pcdo mutant testis but not in the brain. Our data indicate differential requirements for SPAG17 in different motile cilia cell types. SPAG17 is required for proper development of the sperm flagellum, and is essential for either development or stability of the C1 microtubule structure within cilia, but not the brain ependymal cilia. We identified changes in ependymal cilia beating frequency but these did not apparently alter lateral ventricle cerebrospinal fluid (CSF) flow. Aqueductal (Aq) stenosis resulted in significantly slower and abnormally directed CSF flow and we suggest this is the root cause of the hydrocephalus. The Spag17Pcdo homozygous mutant mice are generally viable to adulthood, but have a significantly shortened life span with chronic morbidity. Our data indicate that the c.5236A>T Pcdo variant is a hypomorphic allele of Spag17 gene that causes phenotypes related to motile, but not primary, cilia. Spag17Pcdo is a novel and useful model for elucidating the molecular mechanisms underlying development of PCD in the mouse.

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

scholarly journals First person – Zakia Abdelhamed

2020 ◽  
Vol 13 (10) ◽  
pp. dmm047852
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Medical Center ◽  
Early Career ◽  
Human Condition ◽  
First Person ◽  
Hypomorphic Allele ◽  
Early Career Researchers ◽  
Research Associate ◽  
Ciliary Dyskinesia ◽  
Selection Of

ABSTRACTFirst Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Zakia Abdelhamed is first author on ‘A novel hypomorphic allele of Spag17 causes primary ciliary dyskinesia phenotypes in mice’, published in DMM. Zakia is a research associate in the lab of Dr Rolf Stottmann at Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, investigating animal models that recapitulate a human condition for understanding disease pathogenesis.

scholarly journals Paravascular spaces at the brain surface: Low resistance pathways for cerebrospinal fluid flow

2017 ◽  
Vol 38 (4) ◽  
pp. 719-726 ◽  
Author(s):  
Beatrice Bedussi ◽  
Mitra Almasian ◽  
Judith de Vos ◽  
Ed VanBavel ◽  
Erik NTP Bakker
Keyword(s):  
Cerebrospinal Fluid ◽  
Fluid Flow ◽  
Confocal Imaging ◽  
Waste Products ◽  
Cerebrospinal Fluid Flow ◽  
Low Resistance ◽  
Cranial Window ◽  
Brain Surface ◽  
Antegrade Flow ◽  
The Brain

Clearance of waste products from the brain is of vital importance. Recent publications suggest a potential clearance mechanism via paravascular channels around blood vessels. Arterial pulsations might provide the driving force for paravascular flow, but its flow pattern remains poorly characterized. In addition, the relationship between paravascular flow around leptomeningeal vessels and penetrating vessels is unclear. In this study, we determined blood flow and diameter pulsations through a thinned-skull cranial window. We observed that microspheres moved preferentially in the paravascular space of arteries rather than in the adjacent subarachnoid space or around veins. Paravascular flow was pulsatile, generated by the cardiac cycle, with net antegrade flow. Confocal imaging showed microspheres distributed along leptomeningeal arteries, while their presence along penetrating arteries was limited to few vessels. These data suggest that paravascular spaces around leptomeningeal arteries form low resistance pathways on the surface of the brain that facilitate cerebrospinal fluid flow.

scholarly journals Automated Analysis of Cerebrospinal Fluid Flow and Motile Cilia Properties in The Central Canal of Zebrafish Embryos

BIO-PROTOCOL ◽  
2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Olivier Thouvenin ◽  
Yasmine Cantaut-Belarif ◽  
Ludovic Keiser ◽  
François Gallaire ◽  
Claire Wyart
Keyword(s):  
Cerebrospinal Fluid ◽  
Fluid Flow ◽  
Automated Analysis ◽  
Central Canal ◽  
Zebrafish Embryos ◽  
Cerebrospinal Fluid Flow ◽  
Motile Cilia

scholarly journals Interstitial and cerebrospinal fluid exchanging process revealed by phase alternate labeling with null recovery MRI

2021 ◽  
Author(s):  
Anna M Li ◽  
Jiadi Xu
Keyword(s):  
Cerebrospinal Fluid ◽  
Fluid Flow ◽  
Interstitial Fluid ◽  
Interstitial Fluid Flow ◽  
Cerebrospinal Fluid Flow ◽  
Recovery Curves ◽  
Ependymal Layer ◽  
Apparent Diffusion ◽  
The Difference ◽  
The Brain

Purpose: To develop Phase Alternate LAbeling with Null recovery (PALAN) MRI methods for the quantification of interstitial to cerebrospinal fluid flow (ICF) and cerebrospinal to interstitial fluid flow (CIF) in the brain. Method: In both T1-PALAN and apparent diffusion coefficient (ADC)-PALAN MRI methods, the cerebrospinal fluid (CSF) signal was nulled, while the residual interstitial fluid (ISF) was labeled by alternating the phase of pulses. ICF was extracted from the difference between the recovery curves of CSF with and without labeling. Similarly, CIF was measured by the T2-PALAN MRI method by labeling CSF, which took advance of the significant T2 difference between CSF and parenchyma. Results: Both T1-PALAN and ADC-PALAN observed a rapid occurrence of ICF at 67±56 ms and 13±2 ms interstitial fluid transit times, respectively. ICF signal peaked at 1.5 s for both methods. ICF was 1153±270 ml/100ml/min with T1-PALAN in the third and lateral ventricles, which was higher than 891±60 ml/100ml/min obtained by ADC-PALAN. The results of the T2-PALAN suggested the ISF exchanging from ependymal layer to the parenchyma was extremely slow. Conclusion: The PALAN methods are suitable tools to study ISF and CSF flow kinetics in the brain.

Network Analysis of Cerebrospinal Fluid Dynamics

2001 ◽  
Author(s):  
Lili Zheng ◽  
Michael Egnor ◽  
Keith Banninger
Keyword(s):  
Fluid Dynamics ◽  
Cerebrospinal Fluid ◽  
Fluid Flow ◽  
Network Analysis ◽  
Progressive Increase ◽  
Cerebrospinal Fluid Dynamics ◽  
High Failure Rate ◽  
Cerebrospinal Fluid Flow ◽  
Life Threatening ◽  
The Brain

Abstract Hydrocephalus is a group of life threatening disorders of cerebrospinal fluid flow in and around the brain. It is characterized, in most cases, by accumulation of cerebrospinal fluid in the ventricles of the brain and a progressive increase in pressure in the cranium. The etiology has traditionally been ascribed to an imbalance between the formation and absorption of the cerebrospinal fluid (CSF). Based on this understanding, the treatment is to insert a shunt surgically in order to drain the accumulating fluid in the heart or abdomen. This treatment is invasive and has a high failure rate.

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