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Dbx1b Defines the Dorsal Habenular Progenitor Domain in the Zebrafish Epithalamus Benjamin J Dean2, Begum Erdogan1, Joshua T Gamse1,2 and Shu-Yu Wu1*

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Dbx1b Defines the Dorsal Habenular Progenitor Domain in the Zebrafish Epithalamus Benjamin J Dean2, Begum Erdogan1, Joshua T Gamse1,2 and Shu-Yu Wu1* Dean et al. Neural Development 2014, 9:20 http://www.neuraldevelopment.com/content/9/1/20 RESEARCH ARTICLE Open Access Dbx1b defines the dorsal habenular progenitor domain in the zebrafish epithalamus Benjamin J Dean2, Begum Erdogan1, Joshua T Gamse1,2 and Shu-Yu Wu1* Abstract Background: The conserved habenular nuclei function as a relay system connecting the forebrain with the brain stem. They play crucial roles in various cognitive behaviors by modulating cholinergic, dopaminergic and serotonergic activities. Despite the renewed interest in this conserved forebrain region because of its importance in regulating aversion and reward behaviors, the formation of the habenular nuclei during embryogenesis is poorly understood due to their small size and deep location in the brain, as well as the lack of known markers for habenular progenitors. In zebrafish, the bilateral habenular nuclei are subdivided into dorsal and ventral compartments, are particularly large and found on the dorsal surface of the brain, which facilitates the study of their development. Results: Here we examine the expression of a homeodomain transcription factor, dbx1b, and its potential to serve as an early molecular marker of dorsal habenular progenitors. Detailed spatiotemporal expression profiles demonstrate that the expression domain of dbx1b correlates with the presumptive habenular region, and dbx1b-expressing cells are proliferative along the ventricle. A lineage-tracing experiment using the Cre-lox system confirms that all or almost all dorsal habenular neurons are derived from dbx1b-expressing cells. In addition, mutant analysis and pharmacological treatments demonstrate that both initiation and maintenance of dbx1b expression requires precise regulation by fibroblast growth factor (FGF) signaling. Conclusions: We provide clear evidence in support of dbx1b marking the progenitor populations that give rise to the dorsal habenulae. In addition, the expression of dbx1b in the dorsal diencephalon is tightly controlled by FGF signaling. Background Recent study of the habenulae has largely focused on the The habenular nuclei (habenulae) develop in the dorsal ventral habenulae, but interest in the dorsal habenulae is diencephalon of vertebrates. These bilaterally paired nu- increasing [2]. Alterations in dorsal habenular structure clei receive inputs from the limbic system and basal and function during development have been linked to ganglia and send outputs to dopaminergic and seroto- dopamine receptor expression as well as impulsivity, at- nergic centers. Despite their small size, these nuclei play tention, aversion and spatial memory endophenotypes in crucial roles in regulating aversion and reward behaviors rodents [3,4]. In zebrafish, the dorsal habenulae regulate [1]. Moreover, the fact that the habenulae are a nexus fear and aversion [5,6]. Together these studies implicate for monoamine circuits highlights the importance of the dorsal habenulae as a possible mediator of attention this brain region for studies of neuromodulation and multi- deficit hyperactivity disorder (ADHD), depression and circuit integration. anxiety [2]. Interestingly, the dorsal habenulae are also The habenular nuclei can be divided into two function- sites of intense acetylcholine receptor and transporter ally distinct subnuclei alternately referred to as medial and expression and control nicotine intake [7-9]. This raises lateral (mammals) or dorsal and ventral (zebrafish) subnuclei. the possibility of targeting the habenulae as a therapeutic intervention to nicotine addiction. Beyond translational research, the zebrafish habenulae also serve as an excellent * Correspondence: [email protected] 1Department of Biological Sciences, Vanderbilt University, Box 351634 Station model to study the basic mechanisms underlying the B, Nashville, TN 37235-1634, USA development of left-right brain asymmetry. Unlike the Full list of author information is available at the end of the article © 2014 Dean et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Dean et al. Neural Development 2014, 9:20 Page 2 of 9 http://www.neuraldevelopment.com/content/9/1/20 mammalian habenulae, teleost dorsal habenulae are ro- (Additional file 1, panel C). These data suggested that bustly asymmetric in anatomy, gene expression and func- dbx1b could be an early molecular marker for the pre- tional connectivity [10]. sumptive habenulae. Interest in how the dorsal habenulae integrate into cho- Next, we closely examined the expression of dbx1b at linergic and monoaminergic circuitry has put pressure on different developmental stages (Figure 1). At 22 hpf, ex- researchers to understand dorsal habenular development. pression of dbx1b was not yet present in the presumptive Indeed, Beretta et al. [11] have shown that dorsal and ven- habenular region, although the prethalamic and midbrain tral habenular neurons arise from distinct progenitor pop- regions showed strong expression (Figure 1A,B). By 24 hpf, ulations. While progress has been made in describing habenular dbx1b expression appeared (Figure 1C,D) and habenular neurogenesis, differentiation and elaboration of was maintained through at least 96 hpf (Figure 1E-J and processes, there are no known markers for habenular pro- data not shown). Moreover, dbx1b expression remained genitors [12-16]. Therefore, finding marker genes that highest adjacent to the third ventricle of the brain, and label dorsal habenular progenitors will be fundamental to was absent from regions distal to the ventricle by 48 studying how the diverse set of dorsal habenular neurons hpf (Figure 1H and 1J; dorsal views). Because neuronal are generated and integrated into neural circuits under- progenitors are often found in regions adjacent to the pinning aversive behavior as well as pathological addictive ventricle in the developing brain, these data led us to and depressive behaviors. speculate that the dbx1b expression pattern includes The dbx homeodomain transcription factors play a cen- the progenitors of habenular neurons. tral role in regulating progenitor status in several regions in the developing central nervous system, including the Dbx1b labels dorsal habenular progenitors spinal cord [17,18]. However, the upstream regulatory To support the hypothesis that dbx1b-expressing cells pathways that regulate dbx gene-family expression are represent habenular progenitors, we examined if these notknown.Herewereportthatinzebrafish,dbx1b is cells are proliferative. Indeed, as shown by phospho-histone expressed in the dorsal diencephalon where it marks H3 staining at 32 hpf, the dbx1b-positive cells close to the dorsal habenular progenitors, and further, that dorsal ventricular surface were proliferative, which was consist- diencephalic expression of dbx1b is controlled by fibro- ent with progenitor cell identity (Figure 2A-D). To see if blastgrowthfactor(FGF)signaling. dbx1b expression is restricted to progenitors we compared the expression of previously described precursor and Results and discussion neuronal habenular markers. Cxcr4b has been proposed Dbx1b is expressed in the presumptive habenulae as a marker of progenitors as well as post-mitotic habenu- During our ongoing efforts to characterize transcription lar precursors [12]. At 36 hpf, a subset of dbx1b-expressing factors (TFs) that are expressed in the dorsal diencephalic cells co-expressed cxcr4b. Specifically, cxcr4b expression region between 24 and 48 hours post-fertilization (hpf), was restricted to the dorsal half of the dbx1b expression we focused on a family of homeodomain-containing TFs domain leaving a ventral region of dbx1b-only expression encoded by the dbx genes because of their known roles in along the ventricle (Figure 2E-F). At 48 hpf, Elavl3 (also neural progenitors. There are three dbx genes in the zeb- known as HuC) marks post-mitotic neurons. Expression rafish genome, and we carefully examined the expression of Elavl3 and dbx1b was more distinct than cxcr4b and pattern of the two dbx1 paralogs, dbx1a and dbx1b.We dbx1b, with Elavl3 expressed dorsally and laterally while excluded dbx2 from our study because its expression has dbx1b was present medially and ventrally along the ven- been detailed previously [19]. At 28 hpf, dbx1a and dbx1b tricle (Figure 2G-H). Kctd12.1 and Kctd12.2 mark dif- showed similar yet distinct expression patterns (Additional ferent populations of differentiated habenular neurons. file 1). As shown previously [20], dbx1a was expressed in At 72 hpf, neither showed any overlap with dbx1b expres- sharply restricted domains in the diencephalon with sion (Figure 2I-L). Similar results were observed with an- prominent expression in the prethalamus and thalamus other habenular differentiation marker, pou4f1 (or brn3a) (Additional file 1: panel A). Expression of dbx1a and (data not shown). Together these results indicated that dbx1b was similar in the prethalamic region, but in the dbx1b expression is maintained in a proliferative popu- thalamic region dbx1b was expressed at a much lower lation of habenular progenitor cells that reside along the level than
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