Lifelong neurogenesis in vertebrates relies on stem cells producing proliferation zones that contain neuronal precursors with distinct fates. Proliferation zones in the adult zebrafish brain are located in distinct regions along its entire anterior-posterior axis. We show a previously unappreciated degree of conservation of brain proliferation patterns among teleosts, suggestive of a teleost ground plan. Pulse chase labeling of proliferating populations reveals a centrifugal movement of cells away from their places of birth into the surrounding mantle zone. We observe tangential migration of cells born in the ventral telencephalon, but only a minor rostral migratory stream to the olfactory bulb. In contrast, the lateral telencephalic area, a domain considered homologous to the mammalian dentate gyrus, shows production of interneurons and migration as in mammals. After a 46-day chase, newborn highly mobile cells have moved into nuclear areas surrounding the proliferation zones. They often show HuC/D immunoreactivity but importantly also more specific neuronal identities as indicated by immunoreactivity for tyrosine hydroxylase, serotonin and parvalbumin. Application of a second proliferation marker allows us to recognize label-retaining, actively cycling cells that remain in the proliferation zones. The latter population meets two key criteria of neural stem cells: label retention and self renewal.

Post-embryonic neurogenesis is a fundamental feature of the vertebrate brain. However, the level of adult neurogenesis decreases significantly with phylogeny. In the first part of this review, a comparative analysis of adult neurogenesis and its putative roles in vertebrates are discussed. Adult neurogenesis in mammals is restricted to two telencephalic constitutively active zones. On the contrary, non-mammalian vertebrates display a considerable amount of adult neurogenesis in many brain regions. The phylogenetic differences in adult neurogenesis are poorly understood. However, a common feature of vertebrates (fish, amphibians and reptiles) that display a widespread adult neurogenesis is the substantial post-embryonic brain growth in contrast to birds and mammals. It is probable that the adult neurogenesis in fish, frogs and reptiles is related to the coordinated growth of sensory systems and corresponding sensory brain regions. Likewise, neurons are substantially added to the olfactory bulb in smell-oriented mammals in contrast to more visually oriented primates and songbirds, where much fewer neurons are added to the olfactory bulb. The second part of this review focuses on the differences in brain plasticity and regeneration in vertebrates. Interestingly, several recent studies show that neurogenesis is suppressed in the adult mammalian brain. In mammals, neurogenesis can be induced in the constitutively neurogenic brain regions as well as ectopically in response to injury, disease or experimental manipulations. Furthermore, multipotent progenitor cells can be isolated and differentiated in vitro from several otherwise silent regions of the mammalian brain. This indicates that the potential to recruit or generate neurons in non-neurogenic brain areas is not completely lost in mammals. The level of adult neurogenesis in vertebrates correlates with the capacity to regenerate injury, for example fish and amphibians exhibit the most widespread adult neurogenesis and also the greatest capacity to regenerate central nervous system injuries. Studying these phenomena in non-mammalian vertebrates may greatly increase our understanding of the mechanisms underlying regeneration and adult neurogenesis. Understanding mechanisms that regulate endogenous proliferation and neurogenic permissiveness in the adult brain is of great significance in therapeutical approaches for brain injury and disease.

In the adult CNS, neurogenesis takes place in special niches. It is not understood how these niches are formed during development and how they are maintained. In contrast to mammals, stem cell niches are abundant in zebrafish and also found in other parts of the brain than telencephalon. To understand common characteristics of neural stem cell niches in vertebrates, we studied the origin and architecture of a previously unknown stem cell niche using transgenic lines, in vivo imaging, and marker analysis. We show that bipotent stem cells are maintained in a distinct niche in the adult zebrafish cerebellum. Remarkably, the stem cells are not typical glia but instead retain neuroepithelial characteristics. The cerebellar stem cell niche is generated by the coordinated displacement of ventricle and rhombic lip progenitors in a two-step process involving morphogenetic movements and tissue growth. Importantly, the niche and its stem cells still remain in ventricular contact through a previously unknown derivative of the ventricle. Factors propagated in the ventricle are thought to be important regulators of stem cell activity. To test the requirements of one family of important factors, Fibroblast growth factors, we used zebrafish with an inducible dominant-negative Fgf receptor. Inhibition of Fgf signaling leads to significant reduction of stem cell activity. In contrast to the predominant view, adult neural stem cells in nonmammalian vertebrates show more neuroepithelial than glial characteristics. Nevertheless, retained epithelial properties such as distinct polarization and ventricular contact are critical common determinants to maintain neural stem cell activity in vertebrates.

Adult telencephalic neurogenesis is a conserved trait of all vertebrates studied. It has been investigated in detail in rodents, but very little is known about the composition of neurogenic niches and the cellular nature of progenitors in nonmammalian vertebrates. To understand the components of the progenitor zones in the adult zebrafish telencephalon and the link between glial characteristics and progenitor state, we examined whether canonical glial markers are colocalized with proliferation markers. In the adult zebrafish telencephalon, we identify heterogeneous progenitors that reside in two distinct glial domains. We find that the glial composition of the progenitor zone is linked to its proliferative behavior. Analyzing both fast-cycling proliferating cells as well as slowly cycling progenitors, we find four distinct progenitor types characterized by differential expression of glial markers. Importantly, a significant proportion of progenitors do not display typical radial glia characteristics. By blocking or activating Fgf signaling by misexpression of a dominant negative Fgf-receptor 1 or Fgf8a, respectively, we find that ventral and dorsal progenitors in the telencephalon also differ in their requirement for Fgf signaling. Together with data on the expression of Fgf signaling components in the ventricular zone of the telencephalon, this suggests that Fgf signaling directly regulates proliferation of specific subsets of adult telencephalic progenitors in vivo. Taken together our results show that adult neural progenitor cells are heterogeneous with their respect to distribution into two distinct glial domains and their dependence upon Fgf signaling as a proliferative cue in the zebrafish telencephalon.

The gut microbiota is a complex consortium of microorganisms with the ability to influence important aspects of host health and development. Harnessing this “microbial organ” for biomedical applications requires clarifying the degree to which host and bacterial factors act alone or in combination to govern the stability of specific lineages. To address this issue, we combined bacteriological manipulation and light sheet fluorescence microscopy to monitor the dynamics of a defined two-species microbiota within a vertebrate gut. We observed that the interplay between each population and the gut environment produces distinct spatiotemporal patterns. As a consequence, one species dominates while the other experiences sudden drops in abundance that are well fit by a stochastic mathematical model. Modeling revealed that direct bacterial competition could only partially explain the observed phenomena, suggesting that a host factor is also important in shaping the community. We hypothesized the host determinant to be gut motility, and tested this mechanism by measuring colonization in hosts with enteric nervous system dysfunction due to a mutation in the ret locus, which in humans is associated with the intestinal motility disorder known as Hirschsprung disease. In mutant hosts we found reduced gut motility and, confirming our hypothesis, robust coexistence of both bacterial species. This study provides evidence that host-mediated spatial structuring and stochastic perturbation of communities can drive bacterial population dynamics within the gut, and it reveals a new facet of the intestinal host–microbe interface by demonstrating the capacity of the enteric nervous system to influence the microbiota. Ultimately, these findings suggest that therapeutic strategies targeting the intestinal ecosystem should consider the dynamic physical nature of the gut environment.

The morphology of the telencephalon displays great diversity among different vertebrate lineages. Particularly the everted telencephalon of ray-finned fishes shows a noticeably different morphology from the evaginated telencephalon of nonray-finned fishes and other vertebrates. This makes the comparison between the different parts of the telencephalon of ray-finned fishes and other vertebrates difficult. Based on neuroanatomical, neurochemical, and connectional data no consensus on the subdivisions of the adult telencephalon of ray-finned fishes and their relation to nuclei in the telencephalon of other vertebrates has been reached yet. For tetrapods, comparative expression pattern analysis of homologous developmental genes has been a successful approach to clarify homologies between different parts of the telencephalon. In the larval zebrafish, subdivisions of the subpallium have been proposed using conserved developmental gene expression. In this study, we investigate the subdivisions of the adult zebrafish telencephalon by analyzing the expression pattern of conserved molecular marker genes. We identify the boundary between the pallium and subpallium based on the complementary expression of dlx2a, dlx5a in the subpallium and tbr1, neurod in the pallium. Furthermore, combinatorial expression of Isl, nkx2.1b, lhx1b, tbr1, eomesa, emx1, emx2, and emx3 identifies striatal-like, pallidal-like, and septal-like subdivisions within the subpallium. In contrast to previous models, we propose that the striatum and pallidum are stretched along the rostrocaudal axis of the telencephalon. Further, the septal nuclei derive from both the pallium and subpallium. On this basis, we present a new model for the subdivisions of the subpallium in teleost fish.

Sustaining a balanced intestinal microbial community is critical for maintaining intestinal health and preventing chronic inflammation. The gut is a highly dynamic environment, subject to periodic waves of peristaltic activity. We hypothesized that this dynamic environment is a prerequisite for a balanced microbial community and that the enteric nervous system (ENS), a chief regulator of physiological processes within the gut, profoundly influences gut microbiota composition. We found that zebrafish lacking an ENS due to a mutation in the Hirschsprung disease gene, sox10, develop microbiota-dependent inflammation that is transmissible between hosts. Profiling microbial communities across a spectrum of inflammatory phenotypes revealed that increased levels of inflammation were linked to an overabundance of pro-inflammatory bacterial lineages and a lack of anti-inflammatory bacterial lineages. Moreover, either administering a representative anti-inflammatory strain or restoring ENS function corrected the pathology. Thus, we demonstrate that the ENS modulates gut microbiota community membership to maintain intestinal health.

Based on our gene expression data, we propose a new model of subdivisions in the adult zebrafish pallium and their putative homologies to pallial nuclei in tetrapods. Pallial nuclei control sensory, motor, and cognitive functions, like memory, learning and emotion. The identification of pallial subdivisions in the adult zebrafish and their homologies to pallial nuclei in tetrapods will contribute to the use of the zebrafish system as a model for neurobiological research and human neurodegenerative diseases.