ReviewMechanisms of directional asymmetry in the zebrafish epithalamus
Introduction
Asymmetry is a conserved and fundamental feature of the brain that is thought to enhance efficiency in information processing, as specialisation of one hemisphere leaves the opposite free to perform other tasks [1], [2], [3]. Despite its functional relevance and the association of compromised asymmetry to several neuropathologies including schizophrenia, autism and neuronal degenerative diseases [4], [5], [6] the mechanism by which asymmetry is established during development has been largely elusive. Only in the last decade we have started to gain insights into the developmental basis of brain asymmetry owing to the use of genetic model organisms that allow a comprehensive bottom-up (gene to behaviour) approach (e.g. [7], [8], [9], [10]). In vertebrates, one such organism is zebrafish as it offers several practical advantages (reviewed in [10]). First, it is a well-established genetic system in which to explore the role of genes at the various levels of brain asymmetry organisation [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. Second, the transparency of embryos and larvae that exhibit external development allows the visualisation of neuronal and axonal morphogenesis within asymmetric circuits in vivo [16], [17], [21], [22]. Third, the feasibility to assess neuronal activity and behaviour [23], [24], [25], [26], [27], [28], [29] allows the establishment of operational links between lower (genetic, structural) and upper (functional, behavioural) levels of brain lateralisation [10], [30]. Finally, zebrafish offers a unique opportunity to dissect conserved and species-specific mechanisms of brain asymmetry through comparative developmental studies between related teleost species [18], [31].
The best-studied example of asymmetry in the zebrafish brain is observed in the epithalamus, a region of the dorsal diencephalon containing the pineal complex and habenulae (Fig. 1A) (reviewed in [10], [32], [33], [34]). The pineal complex is a photoreceptive neuroendocrine cell group involved in the physiology of circadian rhythms and is formed by pineal and parapineal organs. Although the site of emergence of the pineal stalk shows a subtle displacement to the left [11] the most conspicuous asymmetry of the pineal complex corresponds to the asymmetric positioning of the parapineal organ [12]. During embryogenesis, this neuronal structure stems from the dorsal midline and migrates asymmetrically to the left side of the brain [16], [17]. On the other hand, the habenulae is a paired bilateral structure that serves as a relay station linking the limbic forebrain and the ventral midbrain (reviewed in [32], [33], [35], [36]). Asymmetries between left and right habenular nuclei are observed at gene and protein expression levels, in the cytoarchitecture and ratio of habenular sub-nuclei, and in the morphology and connectivity of habenular projection neurons [12], [15], [16], [17], [20], [21], [22], [37], [38].
Three specific features are central in the genetic control of epithalamic asymmetry. First, epithalamic asymmetry belongs to the class of directional or population-level asymmetry, as it is inherited and most individuals are asymmetrical in the same direction within the population [39], [40]. Indeed, parapineal and habenular asymmetries are directed to the left side in more than 95% of the wild type zebrafish population [11], [12]. This fact raises the question of whether the two main aspects of directional asymmetry, asymmetry per se and laterality (directionality) of asymmetry are controlled by common or independent genetic pathways (Fig. 1B). Second, laterality of epithalamic asymmetry is coupled to laterality of visceral asymmetry [11], [12], [13], [18], [31]. This observation raises the question of when, where and how the genetic pathways that control brain and visceral asymmetries meet and in which situations they become uncoupled. Finally, asymmetries of the parapineal organ and habenulae develop sequentially and their interactions mutually enhance individual asymmetries and the final configuration of lateralised circuits [12], [16], [17], [31]. These findings raise the possibility that epithalamic asymmetry is organised into functional ontogenic modules that interact during development in a causally dependent manner. Altogether, addressing the questions outlined above is fundamental to understand the developmental and evolutionary mechanisms of epithalamic asymmetry [32], [41] and may also provide insights into the ontogeny of other types of brain asymmetries that are not coupled to the viscera, e.g. asymmetries associated to speech and handedness [42], [43], [44].
Section snippets
Establishing directional asymmetry in the epithalamus
Directional asymmetry can be achieved in one of two possible ways. A common mechanism may simultaneously control the establishment of asymmetry and laterality (Fig. 1B-1). Alternatively, a primary mechanism may establish individual-level asymmetry (expressed at a population-level as random asymmetry or anti-symmetry) (Fig. 1B-2) whereas a second mechanism controls the laterality of asymmetry to favour one of two possible outcomes (Fig. 1B-3) [39], [40], [41]. The first distinction between these
Mechanisms of asymmetric morphogenesis
We have shown that the output of the Nodal-modulated Fgf8-dependent bi-stable system is the left-sided migration of the parapineal organ. As this event is a process of asymmetric morphogenesis per se the bi-stable system provides a direct link between the mechanisms that establish directional asymmetry and those involving asymmetric morphogenesis (Fig. 2, Fig. 6). In addition, the parapineal organ is causally involved in the amplification of habenular asymmetries and in the establishment of
Organisation of epithalamic asymmetry into a sequence of developmental modules
Genetic and morphogenetic mechanisms involved in the ontogeny of epithalamic asymmetry meet several criteria to propose they organise into a sequence of developmental modules (Fig. 6). First, they form discrete entities whose functions are separable from those of other entities (modules) [83], [84], [85]. In addition, they are dynamic units that change over ontogenic time and are able to induce changes in other modules [84], [86], [87]. Moreover, they show strong internal integration (within
The evolutionary origin of epithalamic asymmetry
Current knowledge is consistent with the idea that the epithalamic region was present in chordates prior to the origin of vertebrates (discussed in [32]). However, when and how asymmetry first appeared during evolution remains unclear. The presence of paired and sometimes asymmetric pineal foramens in fossils of Ostracoderm fish [92], [93], [94] suggests that the pineal complex was originally a paired structure and that asymmetries may have appeared early in evolution. Based on these findings,
Concluding remarks
The epithalamus of zebrafish is a valuable model of directional asymmetry in vertebrates. Asymmetry is inherited, shows consistent laterality at a population-level and is coupled to asymmetries of the viscera. The mechanisms underlying the establishment of epithalamic asymmetry are organised into distinct developmental modules that are arranged in a causally dependent sequential manner. A left-sided laterality signal dependent on asymmetries of the LPM influences the outcome of the
Acknowledgements
We are particularly grateful to Nohema Contreras for her valuable help in drawing the figures, and Steve Wilson, Néstor Guerrero, Pablo Oteíza and Germán Reig for critical reading of the manuscript. Work on the epithalamus and asymmetry in our group is supported by the Howard Hughes Medical Institute (HHMI INTNL 55005940), the Chilean Commission of Science and Technology (PBCT ACT47, BMBF/CONICYT 2003-4-124), the Millennium Scientific Initiative (ICM P07-048-F), and a grant from the European
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These authors contributed equally.