Archives for RIKEN Jun Aruga Laboratory (Lab for Comparative Neurogenesis/Behavioral and Developmental Disorders, 2004-2013)
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There are two main projects, Zic and LRR. This classification is mainly for practical purposes. Both projects deal with neural development and human disorders, and are closely linked each other.
This project can be traced back to 1991, when the laboratory head was a member of Dr. Mikoshiba's laboratory and worked mainly on the role of Zic genes in vertebrate development. The Zic gene family (Zinc finger protein of the cerebellum) (Aruga et al., 1994) is critical for animal development. The major goals of our research projects involve clarifying the molecular mechanisms of Zic-mediated developmental control and phylogenetic analyses to determine structure-function relationships and thus understand their evolutionary significance.
Comparative genomic analysis showed that there are a number of neuronal LRR (leucine-rich repeat) proteins with unknown function, despite the importance of other known LRR proteins (Slit, Ntrk, some Drosophila proteins, etc.). Various neuronal LRR proteins are also involved in neuropsychiatric disorders, further indicating their importance in higher brain function. Our first priority was the generation of mutant animals, allowing molecular analysis following initial characterization. We have started the analysis of Slitrk and Lrfn family proteins, both of which are important for brain functions. We are now extending the analysis to other LRR protein families, hoping that the mutant mice collection will be a nation-wide resource for the neurobiological studies.
Conceptually, above research projects are dealing with following scientific themes.
1. Molecular mechanisms underlying the differentiation and proliferation of neural/embryonic stem cells
Zic family nuclear proteins possess a mysterious character: they are highly versatile and can regulate the expression of many genes. These family proteins participate in several stages of neurogenesis including neural induction (neural plate formation) and neurulation (neural tube formation) as well as regional specification of the neural tube and neural circuit formation. We recently discovered several binding partners for Zic proteins, and now are working to how these binding partners combine to regulate proliferation and differentiation of embryonic stem cells and neural stem cells. Clarifying Zic-mediated regulation will contribute to not only to the understanding of the molecular basis of neurogenesis but also improve technological efforts to use the stem cells.
2. Global information processing systems in mammalian brain
Neuronal cell membranes seem to have adapted to information processing, bearing many neural cell-specific or -enriched transmembrane proteins. Neural LRR proteins are major constituents of this category, and are known to be involved in the neurite extension, axonal guidance, synapse formation, and modulation of synaptic functions. These functions are mostly essential for higher brain function. We are currently focusing the synapse maturation, regulation of monoamine or neurotrophin-mediated signaling. These cellular and molecular events are associated with broad range of neuronal subtypes, facilitating us to approach general aspects of neuronal function.
3. Molecular pathogenesis of the neurodevelopmental and neuropsychiatric disorders
Our mutant mice are firstly comprehensively analyzed in terms of their behavioral properties. The reason why we emphasize the behavioral analysis is that higher brain function abnormalities are most easily detected by the behavioral abnormalities in our experiences. Most mutant mice that are generated in our laboratory (>10) show behavioral abnormalities. The abnormalities are often similar to some aspects of the neuropsychiatric disorders (e.g. schizophrenia, affective disorders) and neurodevelopmental disorders (e.g. autism-spectrum disorders). Therefore, the detailed analysis of the targeted mice is beneficial for the understanding pathogenesis of these disorders. In this regard, our strategy can be summarized as a comparative genomics-based hypothesis driven approach.
Below table lists some of the genes that we have identified and analyzed. These genes are causal genes for various neuronal disorders. We are broadening our analysis by collaborating human clinical geneticists so that we can determine whether our targeted genes directly contribute to the human disorders.
4. Evolution of the nervous system
The origin and evolution of the human brain is a challenging topic in neurobiology that we are tackling by examining the genomic information common between animal nervous systems. Molecular phylogenetic analyses that encompass a diverse set of animals successfully identified new protein domains which could not be functionally characterized. We believe that the selective loss of the conserved domains acquired in an ancestral animal may contribute to the diversification of body organization, including the nervous system (see a relevant essay) . We tested this idea by analyzing protein function in model animals. Besides conducting protein-coding region analysis, comparative genomics analysis can expose those DNA sequences that control gene expression. Gene comparisons between vertebrate animals identified a number of DNA sequences required for gene expression at various developmental stages and places. These regulatory DNA sequences interact to generate a very sophisticated gene expression profile of a neural gene.
As we conducted our comparative genomics analyses, we accumulated genetic material (DNA, RNA, and genomic libraries) that may be useful for other molecular phylogenetic analysis. In particular, we were able to compare gene targets in various invertebrate nervous systems from the materials gathered from these animals. If you would like to use these materials (see Photos), send us a request by clicking here.