Common and Distinct Features of Adult Neurogenesis and Regeneration in the Telencephalon of Zebrafish and Mammals

Abstract

In contrast to mammals, the adult zebrafish brain shows neurogenic activity in a multitude of niches present in almost all brain subdivisions. Irrespectively, constitutive neurogenesis in the adult zebrafish and mouse telencephalon share many similarities at the cellular and molecular level. However, upon injury during tissue repair, the situation is entirely different. In zebrafish, inflammation caused by traumatic brain injury or by induced neurodegeneration initiates specific and distinct neurogenic programs that, in combination with signaling pathways implicated in constitutive neurogenesis, quickly, and efficiently overcome the loss of neurons. In the mouse brain, injury-induced inflammation promotes gliosis leading to glial scar formation and inhibition of regeneration. A better understanding of the regenerative mechanisms occurring in the zebrafish brain could help to develop new therapies to combat the debilitating consequences of brain injury, stroke, and neurodegeneration. The aim of this review is to compare the properties of neural progenitors and the signaling pathways, which control adult neurogenesis and regeneration in the zebrafish and mammalian telencephalon.

Keywords: BMP; adult neurogenesis; brain lesion; inflammation; mouse; neural stem cell; notch; zebrafish.

FIGURE 1

Schematic representation of evagination and eversion in vertebrates. The top panel illustrates the telencephalic part of the neural tubes that will evolve differently during development between ray-finned fish (actinopterygians) and other vertebrates. In the latter, the neural tube will follow an evagination process of the telencephalic vesicles (left panel) producing paired telencephalic hemispheres with two internal ventricles (the lateral ventricles in mammals). In contrast, in ray-finned fish (right panel), the neural tube in its dorsal region (pallium) grows and curves laterally. It folds toward the ventral region (subpallium) producing two massive hemispheres flanking a single ventricular cavity. Such movements will stretch the dorsal roof-plate region of the neural tube and will form the tela choroidea. The red parts show the different positioning of the territories following the eversion or evagination processes. The red arrows highlight the movements occurring in the neural tubes. Fp, floor plate; lp, lateral plate; rp, roof plate; vc, ventricular cavity.

FIGURE 2

Anatomy of the zebrafish telencephalon and homologies with the mammal brain. (A) Zebrafish telencephalon indicating the different brain regions and/or nuclei of the pallium and subpallium in the left hemisphere according to Wullimann et al. (1996). The Dm (purple), Dl/Dp (yellow), and Dc (green) have been proposed to be the homologs of the amygdala, hippocampus and the neocortex in rodents (see corresponding colors in the bottom scheme C). The right zebrafish telencephalic hemisphere illustrates the distribution of neural stem/progenitor cells with type 1 (quiescent RGCs), type 2 (proliferative RGCs) and type 3 cells (neuroblasts). (B) Molecular features/markers of type 1, 2, and 3 cells are indicated below the scheme. Bold writing corresponds to strong expression of the proteins. (C) Mouse transversal section through the telencephalon and diencephalon indicating the corresponding homologies with the zebrafish telencephalon. Am, amygdala; Dc, central zone of the dorsal telencephalon; Dl, lateral zone of the dorsal telencephalon; Dm, dorsomedial zone of the dorsal telencephalon; Dp, posterior zone of the dorsal telencephalon; Hipp, hippocampus; Vv, ventral nucleus of the ventral telencephalon; Vd, dorsal nucleus of the ventral telencephalon.

FIGURE 3

Neurogenic niches in the brain of mammals and zebrafish. (A) Sagittal section of a rodent brain illustrating the main proliferative area shown by red dots (top scheme). The two black lines correspond to coronal sections through the subventricular zone (SVZ) of the lateral ventricles (middle scheme) and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus (bottom scheme). The red dots correspond to proliferative cells. (B) Sagittal brain section of a zebrafish brain illustrating the main proliferative areas shown by red dots (top scheme). The two black lines correspond to coronal sections through the anterior part of the telencephalon, where the ventricular zone of the Vv-Vd is suggested to be the equivalent of the SVZ in mammals (middle scheme), and through the medial part of the telencephalon, where the Dl/Dp is suggested to be the homolog of the hippocampus in mammals (bottom scheme). In zebrafish, the red dots correspond to slow cycling progenitors (mainly RGCs, type 2) and the green ones to fast cycling progenitors (mainly neuroblasts, type 3). Ce, cerebellum; D, telencephalic dorsal area; OB, olfactory bulbs; Hyp, hypothalamus.

FIGURE 4

Type of divisions of neural stem/progenitor cells and injury-induced proliferation in the telencephalon of adult zebrafish. Left panel: Symmetric gliogenic division (A) in which one dividing RGC provides two new RGCs. A RGC can also divide asymmetrically (B), self-renew and generate a non-glial progenitor (neuroblast). Another possible type of division is the symmetric non-gliogenic division (C) in which one RGC provides two non-glial progenitors. Finally, direct conversion of a RGC into a neuron can also occur (D). The non-glial progenitors can give rise to new neurons through direct conversion (Dc) or indirect conversion (Ic). Right panel: Injury-induced proliferation following traumatic injury in the brain of adult zebrafish (E). In the intact hemisphere (right part), most RGCs are quiescent (type 1) and some are proliferating (type 2). There are also a number of non-glial progenitors in the pallium. Five days after stab wound injury (left part), RGCs actively divide and generate numerous non-glial progenitors (type 3) that will provide new neurons to replace the damaged and dying ones.

FIGURE 5

Notch signaling pathway in zebrafish and mouse. Upon interaction between the Notch receptor and its ligands Jagged/Delta, and through several subsequent cleavage steps the NICD is released and translocates to the nucleus. In the nucleus, the NICD, together with Rbpj, activates the expression of the downstream genes Hes (mouse) and her (zebrafish). The Hes/Her proteins bind as homodimers to the promoter of proneural genes to inhibit neuronal fate. Additionally, the dimer can bind to its own promoter, resulting in a negative auto-regulation. bHLH, basic helix-loop-helix; Her, human epidermal growth factor receptor; Hes, Hairy/enhancer of split; NEXT, Notch extracellular truncation; NICD, Notch intracellular domain; Rbpj, Recombining binding protein suppressor of hairless.

FIGURE 6

Differential expression of Hes1 and Ascl1 controls NSC fate. When BMP and Notch signaling are active, the negative autoregulation of Hes1 is repressed and its expression is constantly high, leading to quiescent NSCs. The negative autoregulatory effect of Hes1 is high when BMP signaling is not active, causing Hes1 and Ascl1 to oscillate. Through this oscillation the NSCs are activated and proliferating. In the case of inactive Notch signaling, the repression of Hes1 on Ascl1 is abolished and the NSCs develop into neuroblasts. Ascl; achaete-scute like.

FIGURE 7

BMP signaling pathway in mouse and zebrafish. BMP proteins bind as dimers to a transmembrane receptor complex, formed by BMPR-I and BMPR-II. Through this binding, which can be blocked by extracellular inhibitors like Noggin, a phosphorylation cascade is initiated leading to the phosphorylation of the Smad1/5/8 proteins. The activated Smad1/5/8 forms a complex with Smad4 which interacts in the nucleus with specific co-factors to bind to the regulatory sequences of downstream genes, such as id1. BMP, bone morphogenetic protein; BMPR, BMP receptor; id1, inhibitor of DNA binding 1.

FIGURE 8

BMP and Notch signaling in quiescent RGCs/NSCs. Notch signaling activates gene transcription of Hes in mouse and its zebrafish ortholog her. The Hes/Her proteins form a homodimer which can bind to its own promoter and therefore block its own transcription in a negative feedback loop. BMP signaling activates the transcription of its downstream effector id1. The Id1 protein forms a complex with Hes/Her which inhibits the negative regulatory feedback loop of Hes/Her. BRE, BMP responsive element.