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Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus

BACKGROUND: Hydrocephalus (increased ventricular size due to CSF accumulation) is a common finding in human ciliopathies and in mouse models with genetic depletion of the multiciliated cell (MCC) cilia machinery. However, the contribution of MCC to CSF dynamics and, the mechanism by which impaired M...

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Autores principales: Xue, Yuechuan, Gursky, Zachary, Monte, Brittany, Koundal, Sunil, Liu, Xiaodan, Lee, Hedok, Michurina, Tatyana V., Mellanson, Kennelia A., Zhao, Lucy, Nemajerova, Alice, Kahle, Kristopher T., Takemaru, Ken-Ichi, Enikolopov, Grigori, Peunova, Natalia I., Benveniste, Helene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898469/
https://www.ncbi.nlm.nih.gov/pubmed/35248089
http://dx.doi.org/10.1186/s12987-022-00319-x
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author Xue, Yuechuan
Gursky, Zachary
Monte, Brittany
Koundal, Sunil
Liu, Xiaodan
Lee, Hedok
Michurina, Tatyana V.
Mellanson, Kennelia A.
Zhao, Lucy
Nemajerova, Alice
Kahle, Kristopher T.
Takemaru, Ken-Ichi
Enikolopov, Grigori
Peunova, Natalia I.
Benveniste, Helene
author_facet Xue, Yuechuan
Gursky, Zachary
Monte, Brittany
Koundal, Sunil
Liu, Xiaodan
Lee, Hedok
Michurina, Tatyana V.
Mellanson, Kennelia A.
Zhao, Lucy
Nemajerova, Alice
Kahle, Kristopher T.
Takemaru, Ken-Ichi
Enikolopov, Grigori
Peunova, Natalia I.
Benveniste, Helene
author_sort Xue, Yuechuan
collection PubMed
description BACKGROUND: Hydrocephalus (increased ventricular size due to CSF accumulation) is a common finding in human ciliopathies and in mouse models with genetic depletion of the multiciliated cell (MCC) cilia machinery. However, the contribution of MCC to CSF dynamics and, the mechanism by which impaired MCC function leads to hydrocephalus remains poorly understood. The aim of our study was to examine if defects in MCC ciliogenesis and cilia-generated CSF flow impact central nervous system (CNS) fluid homeostasis including glymphatic transport and solute waste drainage. METHODS: We used two distinct mouse models of MCC ciliopathy: MCC-specific CEP164 conditional knockout mice (FOXJ1-Cre;CEP164(fl/fl) (N = 10), 3-month-old) and p73 knock-out (p73(−/−) (N = 8), 5-month-old) mice. Age-matched, wild-type littermates for each of the mutants served as controls. Glymphatic transport and solute drainage was quantified using in vivo T1 mapping by magnetic resonance imaging (MRI) after CSF infusion of gadoteric acid. Brain morphometry and aquaporin 4 expression (AQP4) was also assessed. Intracranial pressure (ICP) was measured in separate cohorts. RESULTS: In both of the two models of MCC ciliopathy we found the ventriculomegaly to be associated with normal ICP. We showed that FOXJ1-Cre;CEP164(fl/fl) mice with hydrocephalus still demonstrated sustained glymphatic transport and normal AQP4 expression along capillaries. In p73(−/−) mice glymphatic transport was even increased, and this was paralleled by an increase in AQP4 polarization around capillaries. Further, solute drainage via the cribriform plate to the nasal cavity was severely impaired in both ciliopathy models and associated with chronic rhinitis and olfactory bulb hypoplasia. CONCLUSIONS: The combination of sustained glymphatic transport, impaired solute drainage via the cribriform plate to the nasal cavity and hydrocephalus has not previously been reported in models of MCC ciliopathy. Our data enhance our understanding of how different types of ciliopathies contribute to disruption of CNS fluid homeostasis, manifested in pathologies such as hydrocephalus. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12987-022-00319-x.
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spelling pubmed-88984692022-03-17 Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus Xue, Yuechuan Gursky, Zachary Monte, Brittany Koundal, Sunil Liu, Xiaodan Lee, Hedok Michurina, Tatyana V. Mellanson, Kennelia A. Zhao, Lucy Nemajerova, Alice Kahle, Kristopher T. Takemaru, Ken-Ichi Enikolopov, Grigori Peunova, Natalia I. Benveniste, Helene Fluids Barriers CNS Research BACKGROUND: Hydrocephalus (increased ventricular size due to CSF accumulation) is a common finding in human ciliopathies and in mouse models with genetic depletion of the multiciliated cell (MCC) cilia machinery. However, the contribution of MCC to CSF dynamics and, the mechanism by which impaired MCC function leads to hydrocephalus remains poorly understood. The aim of our study was to examine if defects in MCC ciliogenesis and cilia-generated CSF flow impact central nervous system (CNS) fluid homeostasis including glymphatic transport and solute waste drainage. METHODS: We used two distinct mouse models of MCC ciliopathy: MCC-specific CEP164 conditional knockout mice (FOXJ1-Cre;CEP164(fl/fl) (N = 10), 3-month-old) and p73 knock-out (p73(−/−) (N = 8), 5-month-old) mice. Age-matched, wild-type littermates for each of the mutants served as controls. Glymphatic transport and solute drainage was quantified using in vivo T1 mapping by magnetic resonance imaging (MRI) after CSF infusion of gadoteric acid. Brain morphometry and aquaporin 4 expression (AQP4) was also assessed. Intracranial pressure (ICP) was measured in separate cohorts. RESULTS: In both of the two models of MCC ciliopathy we found the ventriculomegaly to be associated with normal ICP. We showed that FOXJ1-Cre;CEP164(fl/fl) mice with hydrocephalus still demonstrated sustained glymphatic transport and normal AQP4 expression along capillaries. In p73(−/−) mice glymphatic transport was even increased, and this was paralleled by an increase in AQP4 polarization around capillaries. Further, solute drainage via the cribriform plate to the nasal cavity was severely impaired in both ciliopathy models and associated with chronic rhinitis and olfactory bulb hypoplasia. CONCLUSIONS: The combination of sustained glymphatic transport, impaired solute drainage via the cribriform plate to the nasal cavity and hydrocephalus has not previously been reported in models of MCC ciliopathy. Our data enhance our understanding of how different types of ciliopathies contribute to disruption of CNS fluid homeostasis, manifested in pathologies such as hydrocephalus. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12987-022-00319-x. BioMed Central 2022-03-05 /pmc/articles/PMC8898469/ /pubmed/35248089 http://dx.doi.org/10.1186/s12987-022-00319-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Xue, Yuechuan
Gursky, Zachary
Monte, Brittany
Koundal, Sunil
Liu, Xiaodan
Lee, Hedok
Michurina, Tatyana V.
Mellanson, Kennelia A.
Zhao, Lucy
Nemajerova, Alice
Kahle, Kristopher T.
Takemaru, Ken-Ichi
Enikolopov, Grigori
Peunova, Natalia I.
Benveniste, Helene
Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus
title Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus
title_full Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus
title_fullStr Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus
title_full_unstemmed Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus
title_short Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus
title_sort sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898469/
https://www.ncbi.nlm.nih.gov/pubmed/35248089
http://dx.doi.org/10.1186/s12987-022-00319-x
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