TY - JOUR AB - The zebrafish has recently become a source of new data on the mechanisms of neural stem cell (NSC) maintenance and ongoing neurogenesis in adult brains. In this vertebrate, neurogenesis occurs at high levels in all ventricular regions of the brain, and brain injuries recover successfully, owing to the recruitment of radial glia, which function as NSCs. This new vertebrate model of adult neurogenesis is thus advancing our knowledge of the molecular cues in use for the activation of NSCs and fate of their progeny. Because the regenerative potential of somatic stem cells generally weakens with increasing age, it is important to assess the extent to which zebrafish NSC potential decreases or remains unaltered with age. We found that neurogenesis in the ventricular zone, in the olfactory bulb, and in a newly identified parenchymal zone of the telencephalon indeed declines as the fish ages and that oligodendrogenesis also declines. In the ventricular zone, the radial glial cell population remains largely unaltered morphologically but enters less frequently into the cell cycle and hence produces fewer neuroblasts. The neuroblasts themselves do not change their behavior with age and produce the same number of postmitotic neurons. Thus, decreased neurogenesis in the physiologically aging zebrafish brain is correlated with an increasing quiescence of radial glia. After injuries, radial glia in aged brains are reactivated, and the percentage of cell cycle entry is increased in the radial glia population. However, this reaction is far less pronounced than in younger animals, pointing to irreversible changes in aging zebrafish radial glia. AU - Edelmann, K. AU - Glashauser, L. AU - Sprungala, S. AU - Hesl, B. AU - Fritschle, M. AU - Ninkovic, J. AU - Godinho, L.* AU - Chapouton, P. C1 - 26312 C2 - 32168 SP - 3099-3115 TI - Increased radial glia quiescence, decreased reactivation upon injury and unaltered neuroblast behavior underlie decreased neurogenesis in the aging zebrafish telencephalon. JO - J. Comp. Neurol. VL - 521 IS - 13 PB - Wiley-Blackwell PY - 2013 SN - 0021-9967 ER - TY - JOUR AB - The corticotropin-releasing hormone (CRH) and its type 1 receptor (CRHR1) play a central role in coordinating the endocrine, autonomic, and behavioral responses to stress. A prerequisite to functionally dissect the complexity of the CRH/CRHR1 system is to unravel the identity of CRHR1-expressing neurons and their connectivities. Therefore, we used a knockin approach to genetically label CRHR1-expressing cells with a tau-lacZ (tZ) reporter gene. The distribution of neurons expressing β-galactosidase in the brain and the relative intensity of labeling is in full accordance with previously described Crhr1 mRNA expression. Combining the microtubule-binding properties of TAU with the Cre-loxP system allowed to direct the β-galactosidase to proximal dendrites, and in particular to axons. Thereby, we were able to visualize projections of CRHR1 neurons such as glutamatergic and dopaminergic afferent connections of the striatum and GABAergic CRHR1-expressing neurons located within its patch compartment. In addition, the tZ reporter gene revealed novel details of CRHR1 expression in the spinal cord, skin, and eye. CRHR1 expression in the retina prompted the identification of a new physiological role of CRHR1 related to the visual system. Besides its reporter properties, this novel CRHR1 allele comprises the possibility to conditionally restore or delete CRHR1 via Flp and Cre recombinase, respectively. Finally, the allele is suitable for further manipulations of the CRHR1 locus by recombinase-mediated cassette exchange. Taken together, this novel mouse allele will significantly facilitate the neuroanatomical analysis of CRHR1 circuits and opens up new avenues to address CRHR1 function in more detail. AU - Kühne, C.* AU - Puk, O. AU - Graw, J. AU - Hrabě de Angelis, M. AU - Schütz, G.* AU - Wurst, W. AU - Deussing, J.M.* C1 - 8400 C2 - 30091 SP - 3150-3180 TI - Visualizing corticotropin-releasing hormone receptor type 1 expression and neuronal connectivities in the mouse using a novel multifunctional allele. JO - J. Comp. Neurol. VL - 520 IS - 14 PB - Wiley-Blackwell PY - 2012 SN - 0021-9967 ER - TY - JOUR AB - All subdivisions of the adult zebrafish brain maintain niches of constitutive neurogenesis, sustained by quiescent and multipotent progenitor populations. In the telencephalon, the latter potential neural stem cells take the shape of radial glia aligned along the ventricle and are controlled by Notch signalling. With the aim of identifying new markers of this cell type and of comparing the effectors of embryonic and adult neurogenesis, we focused on the family of hairy/enhancer of split [E(spl)] genes. We report the expression of seven hairy/E(spl) (her) genes and the new helt gene in three neurogenic areas of the adult zebrafish brain (telencephalon, hypothalamus, and midbrain) in relation to radial glia, proliferation, and neurogenesis. We show that the expression of most her genes in the adult brain characterizes quiescent radial glia, whereas only few are expressed in progenitor domains engaged in active proliferation or neurogenesis. The low proliferation status of most her-positive progenitors contrasts with the embryonic nervous system, in which her genes are expressed in actively dividing progenitors. Likewise, we demonstrate largely overlapping expression domains of a set of her genes in the adult brain, which is in striking contrast to their distinct embryonic expression profiles. Overall, our data provide a consolidated map of her expression, quiescent glia, proliferation, and neurogenesis in these various subdivisions of the adult brain and suggest distinct regulation and function of Her factors in the embryonic and adult contexts. AU - Chapouton, P. AU - Webb, K.J. AU - Stigloher, C. AU - Alunni, A.* AU - Adolf, B. AU - Hesl, B. AU - Topp, S. AU - Kremmer, E. AU - Bally-Cuif, L. C1 - 6437 C2 - 28691 SP - 1748-1769 TI - Expression of hairy/enhancer of split genes in neural progenitors and neurogenesis domains of the adult zebrafish brain. JO - J. Comp. Neurol. VL - 519 IS - 9 PB - Wiley-Blackwell PY - 2011 SN - 0021-9967 ER - TY - JOUR AB - The upper rhombic lip (URL) of the developing mammalian cerebellum produces different neuronal cell types in a temporal sequence. The first neuronal populations arising from this proliferation zone include the progenitors of the parabrachial, parabigeminal, and laterodorsal-pedunculopontine tegmental hindbrain nuclei. By means of expression analysis, histology, and retrograde neuronal tracing, we have identified the zebrafish homologues of these nuclei, namely, the secondary gustatory/viscerosensory nucleus, the nucleus isthmi, and the superior reticular nucleus, respectively, in the embryonic and larval brain of a stable transgenic wnt1:Gal4-VP16-14 x UAS:GFP zebrafish strain. Combining time-lapse confocal imaging with individual cell tracing, we characterize the migratory behavior of these neuronal precursor populations in detail by revealing their migration path, velocity, and directionality. In addition, we identify neuronal progenitors of the secondary gustatory/viscerosensory nucleus and nucleus isthmi/superior reticular nucleus as belonging to the polysialic acid (PSA)-expressing cell population in the cerebellar plate that migrates in a PSA-dependent manner. Finally, we reveal that circuitries involved in the processing of sensory information (visual, gustatory, general viscerosensory) are already established in the zebrafish larva at day 4 of development. Also the wnt1-expressing pretectal neuronal precursors (not originating from the URL) sending mossy fiber-like projections into the cerebellar corpus are established at that time. In sum, our results show that the origin of neurons of some tegmental hindbrain nuclei, namely, nucleus isthmi/superior reticular nucleus and secondary gustatory/viscerosensory nucleus is in the URL, and that the temporal order of cell types produced by the URL and their developmental program are conserved among vertebrate species. AU - Volkmann, K. AU - Chen, Y.Y.* AU - Harris, M.P.* AU - Wullimann, M.F.* AU - Köster, R.W. C1 - 1141 C2 - 27221 SP - 2794-2817 TI - The zebrafish cerebellar upper rhombic lip generates tegmental hindbrain nuclei by long-distance migration in an evolutionary conserved manner. JO - J. Comp. Neurol. VL - 518 IS - 14 PB - Wiley-Blackwell PY - 2010 SN - 0021-9967 ER - TY - JOUR AB - Serotonin is a major central nervous modulator of physiology and behavior and plays fundamental roles during development and plasticity of the vertebrate central nervous system (CNS). Understanding the developmental control and functions of serotonergic neurons is therefore an important task. In all vertebrates, prominent serotonergic neurons are found in the superior and inferior raphe nuclei in the hindbrain innervating most CNS regions. In addition, all vertebrates except for mammals harbor other serotonergic centers, including several populations in the diencephalon. This, in combination with the intricate and wide distribution of serotonergic fibers, makes it difficult to sort out serotonergic innervation originating from the raphe from that of other serotonergic cell populations. To resolve this issue, we isolated the regulatory elements of the zebrafish raphe-specific gene pet1 and used them to drive expression of an eGFP transgene in the raphe population of serotonergic neurons. With this approach together with retrograde tracing we 1) describe in detail the development, anatomical organization, and projection pattern of zebrafish pet1-positive neurons compared with their mammalian counterparts, 2) identify a new serotonergic population in the ventrolateral zebrafish hindbrain, and 3) reveal some extent of functional subdivisions within the zebrafish superior raphe complex. Together, our results reveal for the first time the specific innervation pattern of the zebrafish raphe and, thus, provide a new model and various tools to investigate further the role of raphe serotonergic neurons in vertebrates. AU - Lillesaar, C. AU - Stigloher, C. AU - Tannhäuser, B. AU - Wullimann, M.F.* AU - Bally-Cuif, L. C1 - 1834 C2 - 25867 SP - 158-182 TI - Axonal projections originating from raphe serotonergic neurons in the developing and adult zebrafish, Danio rerio, using transgenics to visualize raphe-specific pet1 expression. H₂O. JO - J. Comp. Neurol. VL - 512 IS - 2 PB - Wiley-Blackwell PY - 2008 SN - 0021-9967 ER - TY - JOUR AB - In this study we analyze 5-hydroxytryptamine [5-HT]; serotonin) signaling in zebrafish, an increasingly popular vertebrate disease model. We compare and contrast expression of the 5-HT transporter genes slc6a4a and slc6a4b, which identify 5-HT-producing neurons and three novel 5-HT receptors, htr1aa, htr1ab, and htr1bd. slc6a4a and slc6a4b are expressed in the raphe nuclei, retina, medulla oblongata, paraventricular organ, pretectal diencephalic complex, and caudal zone of the periventricular hypothalamus, in line with the expression profiles of homologues from other vertebrates. Our analysis of serotonin transporter (SERT)-encoding genes also identifies parallel genetic pathways used to build the 5-HT system in zebrafish. In cells in which 5-HT is synthesized by tph1, slc6a4b is used for re-uptake, whereas tph2-positive cells utilize slc6a4a. The receptors htr1aa, htr1ab, and htr1bd also show widespread expression in both the larval and adult brain. Receptor expression is seen in the superior raphe nucleus, retina, ventral telencephalon, optic tectum, thalamus, posterior tuberculum, cerebellum, hypothalamus, and reticular formation, thus implicating 5-HT signaling in several neural circuits. We also examine larval brains double-labeled with 5-HTergic and dopaminergic pathway-specific antibodies, to uncover the identity of some 5-HTergic target neurons. Furthermore, comparison of the expression of transporter and receptor genes also allows us to map sites of autoreceptor activity within the brain. We detect autoreceptor activity in the pretectal diencephalic cluster (htr1aa-, htr1ab-, htr1bd-, and slc6a4a-positive), superior raphe nucleus (htr1aa-, htr1ab-, and slc6a4a-positive), paraventricular organ (htr1aa-, htr1ab-, htr1bd-, and slc6a4b-positive), and the caudal zone of the periventricular hypothalamus (htr1ab- and slc6a4b-positive). AU - Norton, W.H.J. AU - Folchert, A. AU - Bally-Cuif, L. C1 - 3649 C2 - 25855 SP - 521-542 TI - Comparative analysis of serotonin receptor (HTR1A/HTR1B families) and transporter (slc6a4a/b) gene expression in the zebrafish brain. JO - J. Comp. Neurol. VL - 511 IS - 4 PB - Wiley-Blackwell PY - 2008 SN - 0021-9967 ER - TY - JOUR AB - The zebrafish adult brain contains numerous neural progenitors and is a good model to approach the general mechanisms of adult neural stem cell maintenance and neurogenesis. Here we use this model to test for a correlation between Fgf signaling and cell proliferation in adult progenitor zones. We report expression of Fgf signals (fgf3,4,8a,8b,17b), receptors (fgfr1-4), and targets (erm, pea3, dusp6, spry1,2,4, and P-ERK) and document that genes of the embryonic fgf8 synexpression group acquire strikingly divergent patterns in the adult brain. We further document the specific expression of fgf3, fgfr1-3, dusp6, and P-ERK in ventricular zones, which contain neural progenitors. In these locations, however, a comparison at the single-cell level of fgfr/P-ERK expression with bromo-deoxy-uridine (BrdU) incorporation and the proliferation marker MCM5 indicates that Fgf signaling is not specifically associated with proliferating progenitors. Rather, it correlates with the ventricular radial glia state, some of which only are progenitors. Together these results stress the importance of Fgf signaling in the adult brain and establish the basis to study its function in zebrafish, in particular in relation to adult neurogenesis. AU - Topp, C. AU - Stigloher, C. AU - Komisarczuk, A.Z.* AU - Adolf, B. AU - Becker, T.S.* AU - Bally-Cuif, L. C1 - 3584 C2 - 25394 SP - 422-439 TI - Fgf signaling in the zebrafish adult brain: Association of Fgf activity with ventricular zones but not cell proliferation. JO - J. Comp. Neurol. VL - 510 IS - 4 PB - Wiley-Blackwell PY - 2008 SN - 0021-9967 ER - TY - JOUR AB - The mitogen-activated protein kinases (MAPKs), also called extracellular signal-regulated kinases (ERKs), are a group of serine/threonine terminal protein kinases activated downstream of a pleiotrophy of transmembrane receptors. Main intracellular components of the MAPK signalling pathway are the RAF, MEK, and ERK proteins, which work in a cascade of activator and effector proteins. They regulate many fundamental cellular functions, including cell proliferation, cell survival, and cell differentiation by transducing extracellular signals to cytoplasmic and nuclear effectors. To reveal more details about possible activation cascades in this pathway, the present study gives a complete description of the differential expression of Braf, Mek1, Mek2, Mek5, Erk1, Erk2, Erk3, and Erk5 in the adult murine brain by way of in situ hybridization analysis. In this study, we found that each gene is widely expressed in the whole brain, except for Mek2, but each displays a very distinct expression pattern, leading to distinct interactions of the MAPK components within different regions. Most notably we found that 1) Braf and Erk3 are coexpressed in the hippocampus proper, confirming a possible functional interaction; 2) in most forebrain areas, Mek5 and Erk5 are coexpressed; and 3) in the neurogenic regions of the brain, namely, the olfactory bulb and the dentate gyrus, Braf is absent, indicating that other activator proteins have to take over its function. Despite these differences, our results show widespread coexpression of the pathway components, thereby confirming the hypothesis of redundant functions among several MEK and ERK proteins in some regions of the brain. © 2006 Wiley-Liss, Inc. AU - di Benedetto, B. AU - Hitz, C. AU - Hölter, S.M. AU - Kühn, R. AU - Vogt Weisenhorn, D.M. AU - Wurst, W. C1 - 4940 C2 - 24142 SP - 542-556 TI - Differential mRNA distribution of components of the ERK/MAPK signalling cascade in the adult mouse brain. JO - J. Comp. Neurol. VL - 500 IS - 3 PB - Wiley-Blackwell PY - 2007 SN - 0021-9967 ER - TY - JOUR AB - The mammalian retina provides several pathways to relay the information from the photoreceptors to the ganglion cells. Cones feed into ON and OFF cone bipolar cells that excite ON and OFF ganglion cells, respectively. In the "classical" rod pathway, rods feed into rod bipolar cells that provide input to both the ON and the OFF pathway via AII amacrine cells. Recent evidence suggests an alternative rod pathway in which rods directly contact some types of OFF cone bipolar cells. The mouse has become an important model system for retinal research. We performed an immunohistochemical analysis on the level of light and electron microscopy to identify the bipolar cells and ganglion cells that are involved in the alternative rod pathway of the mouse retina. 1) We identify a new bipolar cell type, showing that type 3 OFF cone bipolar cells comprise two distinct cell types, that we termed 3a and 3b. Type 3a cells express the ion channel HCN4. Type 3b bipolar cells represent a hitherto unknown cell type that can be identified with antibodies against the regulatory subunit RIIbeta of protein kinase A. 2) We show that both 3a and 3b cells form flat contacts at cone pedicles and rod spherules. 3) Finally, we identify an OFF ganglion cell type whose dendrites costratify with type 3a and 3b bipolar cell axon terminals. These newly identified cell types represent the basis of a neuronal circuit in the mammalian retina that could provide for an alternative fast rod pathway. AU - Mataruga, A.* AU - Kremmer, E. AU - Müller, F.* C1 - 2971 C2 - 24810 SP - 1123-1137 TI - Type 3a and type 3b OFF cone bipolar cells provide for the alternative rod pathway in the mouse retina. JO - J. Comp. Neurol. VL - 502 IS - 6 PB - Wiley-Blackwell PY - 2007 SN - 0021-9967 ER - TY - JOUR AU - Nieto, M.* AU - Monuki, E.S.* AU - Tang, H.* AU - Imitola, J.* AU - Haubst, N.* AU - Khoury, S.* AU - Cunningham, J.* AU - Götz, M. AU - Walsh, C.A.* C1 - 4620 C2 - 22432 SP - 168-180 TI - Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II-IV of the cerebral cortex. JO - J. Comp. Neurol. VL - 479 PB - Wiley PY - 2004 SN - 0021-9967 ER -