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Genetic and Comparative Approaches to Study Asymmetry and Laterality in the Brain
Summary: Miguel Concha studies the genetic and morphogenetic mechanisms that control the development of left-right asymmetry in the vertebrate brain.
Despite our increasing understanding of the mechanisms that control left–right asymmetry in the heart and viscera, little is known about the genetic and developmental mechanisms that establish lateralized circuitry in the vertebrate brain. An important limitation has been the lack of model organisms with conspicuous asymmetry in the brain that are easy to manipulate and whose cellular processes are readily visualized at early stages of embryogenesis. Our previous analyses in zebrafish revealed that a set of genes become asymmetrically expressed in the forebrain before the development of neuroanatomical asymmetries. These structural asymmetries are phylogenetically conserved among vertebrates and developmentally linked to the asymmetry of the heart and viscera. In addition, they show consistent laterality within the population and are expressed in individuals as left–right biases in differentiation, migration, and connectivity. Thus, zebrafish is a prime vertebrate model organism for elucidation of the complex set of signals and cell behaviors involved in generating asymmetric structures within the brain. Asymmetry is thought to confer advantages for information processing and, ultimately, for species survival; in humans, asymmetry is linked to higher cognitive abilities and to a wide range of disorders, including dyslexia and schizophrenia. Unraveling the mechanisms that control the establishment of asymmetry will therefore deepen our understanding of how the vertebrate brain forms normally and will yield important insights into the origins of certain neuropsychological diseases.
In zebrafish, independent mechanisms, operating in a sequential manner, control the initial establishment of structural differences between left and right sides of the brain (asymmetry) and the directionality (laterality—left or right) of these asymmetries. It is interesting that a similar autonomous control of asymmetry and laterality appears to drive handedness in humans and thus may be a widespread feature of vertebrates. A primary, genetically based mechanism ensures that structural asymmetries are established in the brain. The mechanism involves competitive interactions by which one side of the brain inhibits the ability of the contralateral side to develop as “left.” A second genetic mechanism of brain development involves the asymmetric activation of a conserved genetic pathway controlling asymmetry of the heart and viscera in vertebrates (Nodal signaling) and ensuring that laterality of asymmetry is consistently biased to the same (left) side of the brain. After the initial determination of asymmetry and laterality, neuroanatomical asymmetries develop in the parapineal organ and habenulae and in their associated fiber tracts. The parapineal organ is a single neuronal nucleus that originates at the dorsal midline of the diencephalon and migrates toward the left to become positioned close to the left habenula. As we and others recently showed, interactions between parapineal and habenular precursors during embryogenesis are responsible for generating asymmetries in gene expression and neuropil organization within the habenula and, as a consequence, for a dorsoventral segregation of left–right habenular efferent connectivity in a ventral midbrain target nucleus.
Taken together, these results support a model by which asymmetry and laterality of the brain are established independently at early stages of development. Asymmetric morphogenesis begins with a left-sided migration of the parapineal organ, which mediates the production of a “left identity” signal that changes the “bilateral–right” symmetric default status of the habenula. This is followed by asymmetric morphogenesis of the habenula and, as a consequence, by segregation of habenular efferent connectivity in the ventral midbrain. Several unexplored issues remain to be resolved in this model, some of which we are addressing by combining developmental genetic and comparative approaches.
Searching for Novel Genes and Pathways Involved in Left–Right Asymmetry
Most molecules involved in asymmetric morphogenesis of the epithalamus are likely expressed differentially in the left and right sides of the brain. To identify these molecules, we are pursuing a reverse genetic approach based on subtractive hybridization of mRNAs obtained from left and right hemibrains. We are testing genes obtained by this approach as well as other candidate molecules previously identified in our laboratory for their role in asymmetric morphogenesis of the brain, using gain- and loss-of-function analysis in green fluorescent protein GFP) transgenic zebrafish.
In vivo Analysis of Asymmetric Neuronal Morphogenesis
We are using in vivo confocal imaging in GFP-transgenic zebrafish combined with mathematical image analysis to investigate the cellular mechanisms controlling asymmetric parapineal migration in the brain. Preliminary morphotopological analyses performed at supracellular (pineal and parapineal organ), cellular (parapineal cells), and subcellular (blebs and filopodia) levels reveal that, using relatively simple mathematical algorithms, we are able to tackle new biological questions about asymmetric neuronal morphogenesis. For example, we observed that the initial steps of parapineal migration are accompanied by a dramatic reorganization of cell orientation and polarity, which is followed by the appearance of polarized motility directed to the side (left) of migration. We are expanding our analysis to mutant zebrafish embryos with impaired parapineal migration.
Comparative Approaches of Brain Asymmetry in Vertebrates
The habenular complex forms part of a well-conserved dorsal diencephalic conduction system that serves as a functional link between limbic system–related nuclei and the ventral midbrain. Strikingly, the habenular complexes of a wide range of vertebrate species display conspicuous asymmetries in morphology, neurochemistry, and connectivity, suggesting a fundamental role of habenular asymmetry in limbic system–related behaviors. In some vertebrate groups such as lampreys, teleosts, and lizards, the left side of the habenular complex receives afferent connectivity from the photoreceptive parapineal organ (also called the parietal eye). Even though epithalamic asymmetries are described in a wide range of vertebrate species, the extent to which the neuroanatomical and connection asymmetries described in zebrafish are conserved in other vertebrates remains unclear. Therefore, we are performing comparative genetic, morphological, and connection studies of the epithalamic region in various vertebrate species to dissect the conserved and divergent mechanisms of brain asymmetry.
Last updated August 2007
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