From Genes to Disorders
Brain circuit development is largely attributable to strict genetic or environmental determinants, or the synergistic actions of both. The genome is composed of DNA, the blueprint of life. More than half of the total number genes in the human genome are expressed in the brain (~80% of the total genes in mice are expressed throughout the brain). In this post-genomic sequencing era, elucidating the genetic blueprint in brain development is important. Therefore, we focus on genes that play critical roles in brain development, such as neuronal proliferation, migration, differentiation and maturation. To elucidate the molecular basis of brain development and its disorders, we analyze the involvement of brain development-related genes in the formation and function of synapses and networks. Our study of genes associated with brain development may provide clues to solve the onset mechanism of neurodevelopmental-related neurological and psychiatric disorders.
The study of
Functional analysis of genes related to the development of neurons, synapses and circuits
Data mining of the Cerebellar Development Transcriptome DataBase (CDT-DB) has enabled us to identify numerous genes that show specific spatiotemporal expression patterns during postnatal development of the mouse cerebellum. These genes include CAPS/Calcium-dependent activator protein for secretion (Cadps), Cupidin/Homer2, p130 Crk-associated substrate protein (Cas)/breast cancer anti-estrogen resistance protein 1 (Bcar1), very-KIND/kinase non-catalytic c-lobe domain containing 1 (Kndc1), oligodendrocytic myelin paranodal and inner loop protein (Opalin), and phospholipase D (PLD4). CAPS/Cadps encodes dense-core vesicle associated protein, which enhances the secretion of dense-core vesicle containing brain-derived neurotrophic factor (BDNF). Cupidin/Homer2 encodes a postsynaptic scaffold protein that connects to PPxF motif-containing postsynaptic proteins (e.g. metabotropic glutamate receptor (mGluR) 1alpha and 5, inositol 1,4,5-trisphosphate receptor, Shank, Drebrin, and transient receptor potential cation channel), and regulates postsynaptic signaling and spine morphology. p130Cas/Bcar1 encodes a docking protein carrying many phosphotyrosines to which various molecules related to the Src tyrosine kinase and actin-cytoskeletal signaling pathways bind and regulate neurite outgrowth. Very-KIND/Kndc1 encodes two KIND domains containing brain-specific Ras guanine-nucleotide exchange factor, regulating dendrite outgrowth. Opalin encodes a mammalian-specific central myelin loop protein. PLD4 encodes microglial-specific atypical phospholipase D.
Overall, we think that functional analyses of these cerebellar development-related genes shed light on the molecular mechanisms underlying the development of synapses and circuits in various brain regions, such as the cerebral cortex and hippocampus, as well as the cerebellum.
The study of developmental disorders
Use of animal models to study the neuroscience of developmental disorders
CAPS2/Cadps2 is a protein that regulates the dense-core vesicle exocytosis pathway. Our laboratory has previously shown that CAPS2 promotes the secretion of BDNF, a neurotrophic factor essential for regulating synaptic development and plasticity, and is associated with various psychiatric disorders. We recently detected increased expression of a rare alternative splicing variant of CAPS2 (with deletion of exon3, dex3) in a few patients with autism. Importantly, CAPS2-dex3 was found to be localized in dendrites of neurons (but not in axons), thereby affecting CAPS2-dependent promotion of BDNF secretion from axons. Our studies on a mouse model of autism, in which mice express CAPS2-dex3, has provided evidence of perturbed subcellular localization of CAPS2-dex3 in neurons. These results suggest that increased expression of CAPS2-dex3 causes impaired synaptic development and function, resulting in decreased social interaction and increased anxiety. Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Although the etiology of ASD is still unknown, a combination of multiple genetic factors, or an interaction of genetic, environmental and epigenetic factors is suggested to be the cause. Therefore, use of CAPS2 mouse models in our laboratory may contribute to the understanding of the mechanisms underlying ASD, as well as other neurodevelopmental disorders.
Brain gene database
Neuroinformatics of the genetic basis of cerebellar development
The cerebellar cortical circuit of mammals develops via a series of cellular events in the postnatal stage of development to accomplish the formation of functional circuit architectures. The contribution of genetic factors is thought to be crucial to cerebellar development. To better understand the genetic basis of mouse cerebellar cortical circuit development, our laboratory participates in the BrainTx project. Large amounts of data are collected by comprehensive gene expression analyses of mouse cerebellum during postnatal development via microarray, in situ hybridization, and RT-PCR analyses. The data are then incorporated in the BrainTx based on annotation with gene ontology and/or literature. The BrainTx (URL http://www.cdtdb.neuroinf.jp) is a neuroinformatics database of the RIKEN Neuroinformatics Japan Center (NIJC) and the Japan Node of the International Neuroinformatics Coordination Facility (INCF), which is accessed by many researchers and students from all over the world.
We hypothesized that CAPS2 deficiencies in mice should alter oxytocin release, which should in turn result in impaired social behavior.