Diversity and function of motile ciliated cell types within ependymal lineages of the zebrafish brain

D’Gama, Percival P.; Qiu, Tao; Coşacak, Mehmet İlyas; Rayamajhi, Dheeraj; Konac, Ahsen; Hansen, Jan N.; Ringers, Christa; Acuña‐Hinrichsen, Francisca; Hui, Subhra Prakash; Olstad, Emilie Willoch; Chong, Yan Ling; Lim, Charlton Kang An; Gupta, Amitava Sen; Ng, Chee Peng; Nilges, Benedikt S.; Kashikar, Nachiket D.; Wachten, Dagmar; Liebl, David; Kikuchi, Kazu; Kızıl, Çağhan; Yaksi, Emre; Roy, Sudipto; Jurisch‐Yaksi, Nathalie

doi:10.1016/j.celrep.2021.109775

Cited by 59 publications

(72 citation statements)

References 117 publications

(225 reference statements)

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“…We used single cell transcriptome data from zebrafish telencephalon and the entorhinal cortex or superior frontal gyrus of human brains and human fetus datasets. Five datasets were downloaded from the Gene Expression Omnibus repository and used in the current study: human brain datasets GSE147528 [ 37 ] and microglia datasets [ 38 ], and the zebrafish datasets GSE118577 [ 41 ], GSE124162 [ 40 ], GSE161834 [ 42 ], and GSE186874. See Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease

Coşacak

Bhattarai

Jager

et al. 2022

Cells

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Neurogenesis is significantly reduced in Alzheimer’s disease (AD) and is a potential therapeutic target. Contrary to humans, a zebrafish can regenerate its diseased brain, and thus is ideal for studying neurogenesis. To compare the AD-related molecular pathways between humans and zebrafish, we compared single cell or nuclear transcriptomic data from a zebrafish amyloid toxicity model and its controls (N = 12) with the datasets of two human adult brains (N = 10 and N = 48 (Microglia)), and one fetal brain (N = 10). Approximately 95.4% of the human and zebrafish cells co-clustered. Within each cell type, we identified differentially expressed genes (DEGs), enriched KEGG pathways, and gene ontology terms. We studied synergistic and non-synergistic DEGs to point at either common or uniquely altered mechanisms across species. Using the top DEGs, a high concordance in gene expression changes between species was observed in neuronal clusters. On the other hand, the molecular pathways affected by AD in zebrafish astroglia differed from humans in favor of the neurogenic pathways. The integration of zebrafish and human transcriptomes shows that the zebrafish can be used as a tool to study the cellular response to amyloid proteinopathies. Uniquely altered pathways in zebrafish could highlight the specific mechanisms underlying neurogenesis, which are absent in humans, and could serve as potential candidates for therapeutic developments.

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Section: Methodsmentioning

confidence: 99%

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease

Coşacak

Bhattarai

Jager

et al. 2022

Cells

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“…The wt1a expression in ependymal cells could either reflect a specific developmental state or could indicate the existence of different ependymal subpopulations. This has also been suggested by the use of two enhancer trap lines that labelled distinct subsets of mCP epithelial cells in zebrafish ( Bill et al, 2008 ; Garcia-Lecea et al, 2008 ) and a very recent report using single cell RNA sequencing ( D'Gama et al, 2021 ).…”

Section: Discussionmentioning

confidence: 90%

The Wilms Tumor Gene wt1a Contributes to Blood-Cerebrospinal Fluid Barrier Function in Zebrafish

Hopfenmüller

Perner

Reuter

et al. 2022

Front. Cell Dev. Biol.

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The Wilms tumor suppressor gene Wt1 encodes a zinc finger transcription factor, which is highly conserved among vertebrates. It is a key regulator of urogenital development and homeostasis but also plays a role in other organs including the spleen and the heart. More recently additional functions for Wt1 in the mammalian central nervous system have been described. In contrast to mammals, bony fish possess two paralogous Wt1 genes, namely wt1a and wt1b. By performing detailed in situ hybridization analyses during zebrafish development, we discovered new expression domains for wt1a in the dorsal hindbrain, the caudal medulla and the spinal cord. Marker analysis identified wt1a expressing cells of the dorsal hindbrain as ependymal cells of the choroid plexus in the myelencephalic ventricle. The choroid plexus acts as a blood-cerebrospinal fluid barrier and thus is crucial for brain homeostasis. By employing wt1a mutant larvae and a dye accumulation assay with fluorescent tracers we demonstrate that Wt1a is required for proper choroid plexus formation and function. Thus, Wt1a contributes to the barrier properties of the choroid plexus in zebrafish, revealing an unexpected role for Wt1 in the zebrafish brain.

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“…The mechanism underlying development of communicating hydrocephalus in ciliopathy is still poorly understood. However, an increasing number of reports in mice, Xenopus and zebrafish have shown that the MCC (ependymal cells) lining the cerebral ventricles are important for: (i) CSF ‘near wall’ circulation [ 19 , 20 , 22 ], (ii) transport of nutrients and (iii) secretion of neuropeptides important for directional neural stem cell (NSC) migration (reviewed in Spassky and Meunier, 2017 [ 69 ]). Furthermore, genetic studies in humans with hydrocephalus and ciliopathy mouse models have uncovered defective neural stem cell proliferation including impaired cortical neurogenesis [ 60 – 62 , 70 ].…”

Section: Discussionmentioning

confidence: 99%

“…Another contributor to CSF movement within the CNS involves the motile multi-ciliated cells (MCCs) lining the cerebral ventricles [ 18 , 19 ]. Ex situ studies using organotypic cerebral ventricle explant cultures from rodents and pigs [ 19 ], as well as in vivo experiments in Xenopus [ 20 , 21 ] and zebrafish [ 22 ], have revealed intricate dynamic patterns of CSF flow through the ventricles orchestrated by the MCCs. However, the role of MCCs in CSF transport and CNS fluid regulation is incompletely understood [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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

Xue

Gursky

Monte

et al. 2022

Fluids Barriers CNS

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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;CEP164fl/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;CEP164fl/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.

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Diversity and function of motile ciliated cell types within ependymal lineages of the zebrafish brain

Cited by 59 publications

References 117 publications

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer’s Disease

The Wilms Tumor Gene wt1a Contributes to Blood-Cerebrospinal Fluid Barrier Function in Zebrafish

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

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