mdka Expression Is Associated with Quiescent Neural Stem Cells during Constitutive and Reactive Neurogenesis in the Adult Zebrafish Telencephalon

In contrast to mammals, adult zebrafish display an extraordinary capacity to heal injuries and repair damage in the central nervous system. Pivotal for the regenerative capacity of the zebrafish brain at adult stages is the precise control of neural stem cell (NSC) behavior and the maintenance of the stem cell pool. The gene mdka, a member of a small family of heparin binding growth factors, was previously shown to be involved in regeneration in the zebrafish retina, heart, and fin. Here, we investigated the expression pattern of the gene mdka and its paralogue mdkb in the zebrafish adult telencephalon under constitutive and regenerative conditions. Our findings show that only mdka expression is specifically restricted to the telencephalic ventricle, a stem cell niche of the zebrafish telencephalon. In this brain region, mdka is particularly expressed in the quiescent stem cells. Interestingly, after brain injury, mdka expression remains restricted to the resting stem cell, which might suggest a role of mdka in regulating stem cell quiescenc

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

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

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

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

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

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

Deciphering the regulatory network controlling adult neurogenesis in the telencephalon of Danio rerio

In contrast to mammals, zebrafish display an extensive capacity to generate new neurons and repair injuries of the central nervous system (CNS) at adult stages. During adult neurogenesis, new neurons are formed abundantly from a pool of neural stem cells (NSCs) in order to integrate into existing tissue. Pivotal for the regenerative ability of the zebrafish adult brain is the precise control of NSC behavior and long-term maintenance of the stem cell pool. The balance between quiescent NSCs and activated NSCs is fundamental to the successful functional regeneration of the brain. This balance is controlled by a gene regulatory network (GRN) which is tightly regulated in a spatial and temporal manner through the interplay of different factors including transcription regulators, signaling pathways, key genes and their associated regulatory elements and also small molecules arising from non-coding areas of the genome. Understanding which key players are involved in this regulatory network, how these factors are controlled, how they interact with each other and what their exact function is, will help to comprehend how brain regeneration in the adult zebrafish is facilitated and develop possible strategies for initiating similar regenerative processes in the human brain. Therefore, the overall aim of this thesis was to identify key genes and molecules of this complex GRN and investigate their regulation and function on a molecular level and their expression in the adult zebrafish brain. The gene midkine-a (mdka) was previously shown to be involved in the regeneration of the zebrafish retina, heart and fin. In this work, I investigated its expression pattern in the zebrafish adult telencephalon under constitutive and regenerative conditions and found that mdka expression is specifically restricted to cells in the ventricular zone of the zebrafish telencephalon, a stem cell niche of the zebrafish brain, and its expression pattern is mainly associated with quiescent NSCs. Furthermore, regulatory elements for mdka were identified and can be further investigated regarding their response to signaling pathways and their consequent influence on the cell and time specific expression of mdka. Moreover, micro RNAs (miRNAs), which are small molecules originating from non-coding areas of the genome, that showed an increased expression after injury of the zebrafish brain were investigated for their expression pattern and regulatory role in the GRN. Their increased expression and analysis of targeted genes suggested a role in the control of neuronal genes. However, since miRNAs can regulate a number of different targets, detailed investigation into their role in the GRN is still needed. Overall, this thesis provides different tools and applications for the investigation of the GRN that regulates NSC behavior in the adult zebrafish brain and identifies mdka as one of the key genes in the GRN controlling the proliferative behavior of NSCs and regulating stem cell quiescence

mdka Expression Is Associated with Quiescent Neural Stem Cells during Constitutive and Reactive Neurogenesis in the Adult Zebrafish Telencephalon

In contrast to mammals, adult zebrafish display an extraordinary capacity to heal injuries and repair damage in the central nervous system. Pivotal for the regenerative capacity of the zebrafish brain at adult stages is the precise control of neural stem cell (NSC) behavior and the maintenance of the stem cell pool. The gene mdka, a member of a small family of heparin binding growth factors, was previously shown to be involved in regeneration in the zebrafish retina, heart, and fin. Here, we investigated the expression pattern of the gene mdka and its paralogue mdkb in the zebrafish adult telencephalon under constitutive and regenerative conditions. Our findings show that only mdka expression is specifically restricted to the telencephalic ventricle, a stem cell niche of the zebrafish telencephalon. In this brain region, mdka is particularly expressed in the quiescent stem cells. Interestingly, after brain injury, mdka expression remains restricted to the resting stem cell, which might suggest a role of mdka in regulating stem cell quiescence