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Neurogenesis and Regeneration in Teleost Central Nervous System

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (25 July 2022) | Viewed by 50896

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Dr. Sepand Rastegar

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Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany
Interests: gene regulation; transcription; neurogenesis; zebrafish; regeneration; neural stem cell
Special Issues, Collections and Topics in MDPI journals

Ms. Luisa Lübke

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Assistant Guest Editor

Institute of Biological and Chemical Systems - Biological Information Processing Karlsruhe Institute of Technology, Postfach 3640, D-76021 Karlsruhe, Germany
Interests: developmental biology; zebrafish regeneration; neurogenesis; development of the CNS

Special Issue Information

Dear Colleagues,

In our modern society, neurodegenerative diseases, along with cancer, pose one of the main health threats, as the number of older citizens is rising. These diseases are characterized by a progressive degeneration of neurons, which eventually leads to their death and to the disintegration of the nervous system structure.

Currently, neurodegenerative diseases are incurable, as the available treatments either only manage the symptoms or slow down disease progression.

Deciphering the cellular and molecular mechanisms of adult neurogenesis and regeneration is of great importance because it will eventually allow us to identify specific reactive neurogenesis mechanisms and re-instruct neurogenesis in patients suffering from neurodegenerative conditions.

Lately, zebrafish has become a popular model in biomedical research due to its experimental advantages, the existence of numerous genetic manipulation tools and various genetic resources, and the fact that the genetic basis of most diseases is shared between human and zebrafish.

The present Special Issue aims to summarize some of the latest advances in the field of adult neurogenesis and regeneration, using zebrafish as a model organism. We intend to highlight the key molecular mechanisms involved in neurogenesis, under normal physiological conditions and regenerative conditions, in the zebrafish nervous system, focusing on different regions of the brain, retina, and spinal cord.

Dr. Sepand Rastegar
Dr. Luisa Lübke
Guest Editors

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Keywords

Zebrafish
Adult neurogenesis
Neural stem cells
Glial Cells
Regeneration
Neurodegeneration
Brain injury
Olfactory bulb
Telencephalon
Retina
Optic tectum
Cerebellum
Spinal cord

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Published Papers (10 papers)

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Research

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18 pages, 4011 KiB

Open AccessArticle

auts2 Features and Expression Are Highly Conserved during Evolution Despite Different Evolutionary Fates Following Whole Genome Duplication

by Constance Merdrignac, Antoine Emile Clément, Jérôme Montfort, Florent Murat and Julien Bobe

Cells 2022, 11(17), 2694; https://doi.org/10.3390/cells11172694 - 30 Aug 2022

Cited by 1 | Viewed by 2560

Abstract

The AUTS2 gene plays major roles during brain development and is associated with various neuropathologies including autism. Data in non-mammalian species are scarce, and the aim of our study was to provide a comprehensive analysis of auts2 evolution in teleost fish, which are widely used for in vivo functional analysis and biomedical purposes. Comparative genomics in 78 species showed that auts2a and auts2b originate from the teleost-specific whole genome duplication (TGD). auts2a, which is highly similar to human AUTS2, was almost systematically retained following TGD. In contrast, auts2b, which encodes for a shorter protein similar to a short human AUTS2 isoform, was lost more frequently and independently during evolution. RNA-seq analysis in 10 species revealed a highly conserved profile with predominant expression of both genes in the embryo, brain, and gonads. Based on protein length, conserved domains, and expression profiles, we speculate that the long human isoform functions were retained by auts2a, while the short isoform functions were retained by auts2a and/or auts2b, depending on the lineage/species. auts2a showed a burst in expression during medaka brain formation, where it was expressed in areas of the brain associated with neurodevelopmental disorders. Together, our data suggest a strong conservation of auts2 functions in vertebrates despite different evolutionary scenarios in teleosts. Full article

(This article belongs to the Special Issue Neurogenesis and Regeneration in Teleost Central Nervous System)

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21 pages, 7251 KiB

Open AccessFeature PaperArticle

Ependymal and Neural Stem Cells of Adult Molly Fish (Poecilia sphenops, Valenciennes, 1846) Brain: Histomorphometry, Immunohistochemical, and Ultrastructural Studies

by Doaa M. Mokhtar, Ramy K. A. Sayed, Giacomo Zaccone, Marco Albano and Manal T. Hussein

Cells 2022, 11(17), 2659; https://doi.org/10.3390/cells11172659 - 27 Aug 2022

Cited by 11 | Viewed by 2920

Abstract

This study was conducted on 16 adult specimens of molly fish (Poecilia sphenops) to investigate ependymal cells (ECs) and their role in neurogenesis using ultrastructural examination and immunohistochemistry. The ECs lined the ventral and lateral surfaces of the optic ventricle and their processes extended through the tectal laminae and ended at the surface of the tectum as a subpial end-foot. Two cell types of ECs were identified: cuboidal non-ciliated (5.68 ± 0.84/100 μm²) and columnar ciliated (EC3.22 ± 0.71/100 μm²). Immunohistochemical analysis revealed two types of GFAP immunoreactive cells: ECs and astrocytes. The ECs showed the expression of IL-1β, APG5, and Nfr2. Moreover, ECs showed immunostaining for myostatin, S100, and SOX9 in their cytoplasmic processes. The proliferative activity of the neighboring stem cells was also distinct. The most interesting finding in this study was the glia–neuron interaction, where the processes of ECs met the progenitor neuronal cells in the ependymal area of the ventricular wall. These cells showed bundles of intermediate filaments in their processes and basal poles and were connected by desmosomes, followed by gap junctions. Many membrane-bounded vesicles could be demonstrated on the surface of the ciliated ECs that contained neurosecretion. The abluminal and lateral cell surfaces of ECs showed pinocytotic activities with many coated vesicles, while their apical cytoplasm contained centrioles. The occurrence of stem cells in close position to the ECs, and the presence of bundles of generating axons in direct contact with these stem cells indicate the role of ECs in neurogenesis. The TEM results revealed the presence of neural stem cells in a close position to the ECs, in addition to the presence of bundles of generating axons in direct contact with these stem cells. The present study indicates the role of ECs in neurogenesis. Full article

(This article belongs to the Special Issue Neurogenesis and Regeneration in Teleost Central Nervous System)

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23 pages, 7801 KiB

Open AccessArticle

Molecular and Cellular Analysis of the Repair of Zebrafish Optic Tectum Meninges Following Laser Injury

by Payel Banerjee, Paul Joly, Luc Jouneau, Yan Jaszczyszyn, Mickaël Bourge, Pierre Affaticati, Jean-Pierre Levraud, Pierre Boudinot and Jean-Stéphane Joly

Cells 2022, 11(13), 2016; https://doi.org/10.3390/cells11132016 - 24 Jun 2022

Cited by 1 | Viewed by 3804

Abstract

We studied cell recruitment following optic tectum (OT) injury in zebrafish (Danio rerio), which has a remarkable ability to regenerate many of its organs, including the brain. The OT is the largest dorsal layered structure in the zebrafish brain. In juveniles, it is an ideal structure for imaging and dissection. We investigated the recruited cells within the juvenile OT during regeneration in a Pdgfrβ-Gal4:UAS-EGFP line in which pericytes, vascular, circulating, and meningeal cells are labeled, together with neurons and progenitors. We first performed high-resolution confocal microscopy and single-cell RNA-sequencing (scRNAseq) on EGFP-positive cells. We then tested three types of injury with very different outcomes (needle (mean depth in the OT of 200 µm); deep-laser (depth: 100 to 200 µm depth); surface-laser (depth: 0 to 100 µm)). Laser had the additional advantage of better mimicking of ischemic cerebral accidents. No massive recruitment of EGFP-positive cells was observed following laser injury deep in the OT. This type of injury does not perturb the meninx/brain–blood barrier (BBB). We also performed laser injuries at the surface of the OT, which in contrast create a breach in the meninges. Surprisingly, one day after such injury, we observed the migration to the injury site of various EGFP-positive cell types at the surface of the OT. The migrating cells included midline roof cells, which activated the PI3K-AKT pathway; fibroblast-like cells expressing numerous collagen genes and most prominently in 3D imaging; and a large number of arachnoid cells that probably migrate to the injury site through the activation of cilia motility genes, most likely being direct targets of the FOXJ1a gene. This study, combining high-content imaging and scRNAseq in physiological and pathological conditions, sheds light on meninges repair mechanisms in zebrafish that probably also operate in mammalian meninges. Full article

(This article belongs to the Special Issue Neurogenesis and Regeneration in Teleost Central Nervous System)

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20 pages, 4191 KiB

Open AccessFeature PaperArticle

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

by Mehmet Ilyas Cosacak, Prabesh Bhattarai, Philip L. De Jager, Vilas Menon, Giuseppe Tosto and Caghan Kizil

Cells 2022, 11(11), 1807; https://doi.org/10.3390/cells11111807 - 31 May 2022

Cited by 18 | Viewed by 6882

Abstract

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. Full article

(This article belongs to the Special Issue Neurogenesis and Regeneration in Teleost Central Nervous System)

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23 pages, 4434 KiB

Open AccessArticle

Incomplete Recovery of Zebrafish Retina Following Cryoinjury

by Denisa Džulová, Dylan Lawless, Gaëtan G. Pinton, Nicole A. Renner and Daniel F. Schorderet

Cells 2022, 11(8), 1373; https://doi.org/10.3390/cells11081373 - 18 Apr 2022

Cited by 1 | Viewed by 3516

Abstract

Zebrafish show an extraordinary potential for regeneration in several organs from fins to central nervous system. Most impressively, the outcome of an injury results in a near perfect regeneration and a full functional recovery. Indeed, among the various injury paradigms previously tested in the field of zebrafish retina regeneration, a perfect layered structure is observed after one month of recovery in most of the reported cases. In this study, we applied cryoinjury to the zebrafish eye. We show that retina exposed to this treatment for one second undergoes an acute damage affecting all retinal cell types, followed by a phase of limited tissue remodeling and regrowth. Surprisingly, zebrafish developed a persistent retinal dysplasia observable through 300 days post-injury. There is no indication of fibrosis during the regeneration period, contrary to the regeneration process after cryoinjury to the zebrafish cardiac ventricle. RNA sequencing analysis of injured retinas at different time points has uncovered enriched processes and a number of potential candidate genes. By means of this simple, time and cost-effective technique, we propose a zebrafish injury model that displays a unique inability to completely recover following focal retinal damage; an outcome that is unreported to our knowledge. Furthermore, RNA sequencing proved to be useful in identifying pathways, which may play a crucial role not only in the regeneration of the retina, but in the first initial step of regeneration, degeneration. We propose that this model may prove useful in comparative and translational studies to examine critical pathways for successful regeneration. Full article

(This article belongs to the Special Issue Neurogenesis and Regeneration in Teleost Central Nervous System)

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36 pages, 9434 KiB

Open AccessArticle

Innate Immune Pathways Promote Oligodendrocyte Progenitor Cell Recruitment to the Injury Site in Adult Zebrafish Brain

by Rosario Sanchez-Gonzalez, Christina Koupourtidou, Tjasa Lepko, Alessandro Zambusi, Klara Tereza Novoselc, Tamara Durovic, Sven Aschenbroich, Veronika Schwarz, Christopher T. Breunig, Hans Straka, Hagen B. Huttner, Martin Irmler, Johannes Beckers, Wolfgang Wurst, Andreas Zwergal, Tamas Schauer, Tobias Straub, Tim Czopka, Dietrich Trümbach, Magdalena Götz, Stefan H. Stricker and Jovica Ninkovic Show full author list Hide full author list

Cells 2022, 11(3), 520; https://doi.org/10.3390/cells11030520 - 2 Feb 2022

Cited by 7 | Viewed by 5487

Abstract

The oligodendrocyte progenitors (OPCs) are at the front of the glial reaction to the traumatic brain injury. However, regulatory pathways steering the OPC reaction as well as the role of reactive OPCs remain largely unknown. Here, we compared a long-lasting, exacerbated reaction of OPCs to the adult zebrafish brain injury with a timely restricted OPC activation to identify the specific molecular mechanisms regulating OPC reactivity and their contribution to regeneration. We demonstrated that the influx of the cerebrospinal fluid into the brain parenchyma after injury simultaneously activates the toll-like receptor 2 (Tlr2) and the chemokine receptor 3 (Cxcr3) innate immunity pathways, leading to increased OPC proliferation and thereby exacerbated glial reactivity. These pathways were critical for long-lasting OPC accumulation even after the ablation of microglia and infiltrating monocytes. Importantly, interference with the Tlr1/2 and Cxcr3 pathways after injury alleviated reactive gliosis, increased new neuron recruitment, and improved tissue restoration. Full article

(This article belongs to the Special Issue Neurogenesis and Regeneration in Teleost Central Nervous System)

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23 pages, 7372 KiB

Open AccessArticle

Neuron-Radial Glial Cell Communication via BMP/Id1 Signaling Is Key to Long-Term Maintenance of the Regenerative Capacity of the Adult Zebrafish Telencephalon

by Gaoqun Zhang, Luisa Lübke, Fushun Chen, Tanja Beil, Masanari Takamiya, Nicolas Diotel, Uwe Strähle and Sepand Rastegar

Cells 2021, 10(10), 2794; https://doi.org/10.3390/cells10102794 - 19 Oct 2021

Cited by 18 | Viewed by 5175

Abstract

The central nervous system of adult zebrafish displays an extraordinary neurogenic and regenerative capacity. In the zebrafish adult brain, this regenerative capacity relies on neural stem cells (NSCs) and the careful management of the NSC pool. However, the mechanisms controlling NSC pool maintenance are not yet fully understood. Recently, Bone Morphogenetic Proteins (BMPs) and their downstream effector Id1 (Inhibitor of differentiation 1) were suggested to act as key players in NSC maintenance under constitutive and regenerative conditions. Here, we further investigated the role of BMP/Id1 signaling in these processes, using different genetic and pharmacological approaches. Our data show that BMPs are mainly expressed by neurons in the adult telencephalon, while id1 is expressed in NSCs, suggesting a neuron-NSC communication via the BMP/Id1 signaling axis. Furthermore, manipulation of BMP signaling by conditionally inducing or repressing BMP signaling via heat-shock, lead to an increase or a decrease of id1 expression in the NSCs, respectively. Induction of id1 was followed by an increase in the number of quiescent NSCs, while knocking down id1 expression caused an increase in NSC proliferation. In agreement, genetic ablation of id1 function lead to increased proliferation of NSCs, followed by depletion of the stem cell pool with concomitant failure to heal injuries in repeatedly injured mutant telencephala. Moreover, pharmacological inhibition of BMP and Notch signaling suggests that the two signaling systems cooperate and converge onto the transcriptional regulator her4.1. Interestingly, brain injury lead to a depletion of NSCs in animals lacking BMP/Id1 signaling despite an intact Notch pathway. Taken together, our data demonstrate how neurons feedback on NSC proliferation and that BMP1/Id1 signaling acts as a safeguard of the NSC pool under regenerative conditions. Full article

(This article belongs to the Special Issue Neurogenesis and Regeneration in Teleost Central Nervous System)

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14 pages, 3787 KiB

Open AccessFeature PaperArticle

KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease

by Tohid Siddiqui, Prabesh Bhattarai, Stanislava Popova, Mehmet Ilyas Cosacak, Sanjeev Sariya, Yixin Zhang, Richard Mayeux, Giuseppe Tosto and Caghan Kizil

Cells 2021, 10(10), 2748; https://doi.org/10.3390/cells10102748 - 14 Oct 2021

Cited by 13 | Viewed by 6294

Abstract

Neurogenesis decreases in Alzheimer’s disease (AD) patients, suggesting that restoring the normal neurogenic response could be a disease modifying intervention. To study the mechanisms of pathology-induced neuro-regeneration in vertebrate brains, zebrafish is an excellent model due to its extensive neural regeneration capacity. Here, we report that Kynurenic acid (KYNA), a metabolite of the amino acid tryptophan, negatively regulates neural stem cell (NSC) plasticity in adult zebrafish brain through its receptor, aryl hydrocarbon receptor 2 (Ahr2). The production of KYNA is suppressed after amyloid-toxicity through reduction of the levels of Kynurenine amino transferase 2 (KAT2), the key enzyme producing KYNA. NSC proliferation is enhanced by an antagonist for Ahr2 and is reduced with Ahr2 agonists or KYNA. A subset of Ahr2-expressing zebrafish NSCs do not express other regulatory receptors such as il4r or ngfra, indicating that ahr2-positive NSCs constitute a new subset of neural progenitors that are responsive to amyloid-toxicity. By performing transcriptome-wide association studies (TWAS) in three late onset Alzheimer disease (LOAD) brain autopsy cohorts, we also found that several genes that are components of KYNA metabolism or AHR signaling are differentially expressed in LOAD, suggesting a strong link between KYNA/Ahr2 signaling axis to neurogenesis in LOAD. Full article

(This article belongs to the Special Issue Neurogenesis and Regeneration in Teleost Central Nervous System)

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Review

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15 pages, 1555 KiB

Open AccessReview

Inflammation Regulates the Multi-Step Process of Retinal Regeneration in Zebrafish

by Mikiko Nagashima and Peter F. Hitchcock

Cells 2021, 10(4), 783; https://doi.org/10.3390/cells10040783 - 1 Apr 2021

Cited by 29 | Viewed by 5125

Abstract

The ability to regenerate tissues varies between species and between tissues within a species. Mammals have a limited ability to regenerate tissues, whereas zebrafish possess the ability to regenerate almost all tissues and organs, including fin, heart, kidney, brain, and retina. In the zebrafish brain, injury and cell death activate complex signaling networks that stimulate radial glia to reprogram into neural stem-like cells that repair the injury. In the retina, a popular model for investigating neuronal regeneration, Müller glia, radial glia unique to the retina, reprogram into stem-like cells and undergo a single asymmetric division to generate multi-potent retinal progenitors. Müller glia-derived progenitors then divide rapidly, numerically matching the magnitude of the cell death, and differentiate into the ablated neurons. Emerging evidence reveals that inflammation plays an essential role in this multi-step process of retinal regeneration. This review summarizes the current knowledge of the inflammatory events during retinal regeneration and highlights the mechanisms whereby inflammatory molecules regulate the quiescence and division of Müller glia, the proliferation of Müller glia-derived progenitors and the survival of regenerated neurons. Full article

(This article belongs to the Special Issue Neurogenesis and Regeneration in Teleost Central Nervous System)

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24 pages, 7126 KiB

Open AccessReview

Cellular Mechanisms Participating in Brain Repair of Adult Zebrafish and Mammals after Injury

by Batoul Ghaddar, Luisa Lübke, David Couret, Sepand Rastegar and Nicolas Diotel

Cells 2021, 10(2), 391; https://doi.org/10.3390/cells10020391 - 14 Feb 2021

Cited by 33 | Viewed by 6449

Abstract

Adult neurogenesis is an evolutionary conserved process occurring in all vertebrates. However, striking differences are observed between the taxa, considering the number of neurogenic niches, the neural stem cell (NSC) identity, and brain plasticity under constitutive and injury-induced conditions. Zebrafish has become a popular model for the investigation of the molecular and cellular mechanisms involved in adult neurogenesis. Compared to mammals, the adult zebrafish displays a high number of neurogenic niches distributed throughout the brain. Furthermore, it exhibits a strong regenerative capacity without scar formation or any obvious disabilities. In this review, we will first discuss the similarities and differences regarding (i) the distribution of neurogenic niches in the brain of adult zebrafish and mammals (mainly mouse) and (ii) the nature of the neural stem cells within the main telencephalic niches. In the second part, we will describe the cascade of cellular events occurring after telencephalic injury in zebrafish and mouse. Our study clearly shows that most early events happening right after the brain injury are shared between zebrafish and mouse including cell death, microglia, and oligodendrocyte recruitment, as well as injury-induced neurogenesis. In mammals, one of the consequences following an injury is the formation of a glial scar that is persistent. This is not the case in zebrafish, which may be one of the main reasons that zebrafish display a higher regenerative capacity. Full article

(This article belongs to the Special Issue Neurogenesis and Regeneration in Teleost Central Nervous System)

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