Laboratory of
Molecular and Cellular Neuroscience

IIJIMA LAB
飯島研究室

Principal Investigator:
Takatoshi Iijima (Associate Professor)

Molecular Mechanisms Underlying Neuronal Differentiationand Synaptic Plasticity
Keywords: gene regulation, RNA, alternative splicing, neuron, synapse, autism
Background and Motivation
Brain is highly organized hard-wired system composed of >100 billion of neurons diversified morphologically and functionally. It is still very questionable andmysterious how diversity of neuronal cell types and the resulting complexity of the neural circuit are organized by a quite limited number of genes (<30000genes in human). To the end we have studied the RNA-based regulations by which neural differentiation and plasticity are organized temporally and spatially.
Recently we are specially focusing on alternative splicing – a powerful tool for generating several gene products from a single gene. Molecular diversity has
been suggested to contribute to the complexity and diversity of organisms. Our research goal is to uncover mechanisms of alternative splicing in neurons andthen to explore the physiological relevance of huge molecular diversity by alternative splicing in central nervous system.

Originality
Whereas many scientists have well studied how cells are diversified from a single fertilized egg precisely and how specific cell types are induced efficiently on
stem cell biology with ES or iPS cells, it is still not well understood how differentiated cells are recognized each other to organize the specific network and wellsynergized as a organic system. We are now focusing on alternative splicing as a critical mechanism underlying diversity and specificity of cell-to-cellrecognition. Brain, a hard-wired system composed of huge number of diversified neurons, is much more complicated than any other organs. Therefore, giventhat most of neuronal genes Is highly subjected to alternative splicing, we think that alternative splicing programs in central nervous system would be the mostrepresentative model for studying the physiological relevance of molecular diversity to diversity and specificity in vertebrate.

Impact and Perspective
Significant amount of pre-mRNAs are known to be highly subjected to alternative splicing in not only brain but also other tissues. It is speculated thatalternative splicing could be also controlled in similar fashions by several kinds of external stimuli (temperature, chemical or physical stimuli, food intake,hypoxia, exercise etc.) in non-neuronal tissues. Therefore, the outcome from my project may propose a fundamental model for adaptation, acquired
properties, complexity and diversity of mammalian cells by dynamic regulation of alternative splicing.
It has been revealed that de-regulation of alternative splicing in central nervous system causes several mental diseases (e.g. autism, schizophrenia, bipolardisease), suggesting that the molecular diversity derived from alternative splicing is implicated in our mental activity as emotion and cognition. Therefore,
insight into neuronal circuit deficits in these mice may provide pathological insights into these human disorders and some hints for the clinical therapy.

■ For more information:www.utokai.ac.jp/tuiist/english/tt/announcement_iijima.html■ CONTACT:
Takatoshi Iijima, Ph.D.
Tokai University Institute of Innovative
Science and Technology
Medical Science Division
143 Shimokasuya, Isehara City,
Kanagawa 259-1193 JAPAN
Phone +81(0)463-93-1121 (Ext. 2785)
Fax+81(0)463-95-3522
Email takatoshi.iijima@tokai-u.jp

Fig.2 Activity-dependent alternative splicing decision ofsynapse organising molecules Neurexin-1 by RNA-binding
protein SAM68 and dynamic change in trans-synaptic
interaction of postsynaptic partner’s proteins.
Fig.1 Model of dynamic regulation of synapse formationand functions by neuronal alternative splicing