1: Distinct Roles of Ventromedial versus Ventrolateral Striatal Medium Spiny Neurons in Reward-Oriented Behavior.
Science of the Month - November 2017
Curr Biol.
Tsutsui-Kimura I, Natsubori A, Mori M, Kobayashi K, Drew MR, de Kerchove d'Exaerde A, Mimura M, Tanaka KF.
Neural activity is recorded as changes in electrical potential. We are taught this, and indeed, electroencephalography captures neural activity. However, electrophysiological methods cannot isolate the activity of only the tens of thousands of neural subtypes present in the brain. Therefore, a worldwide challenge began to extract the collective activity of neural subtypes as changes in intracellular calcium concentration. Realizing this idea requires two things: a calcium sensor and a detection system. As a calcium sensor, we used Cameleon, developed by Dr. Atsushi Miyawaki (class of '66), and we newly constructed a calcium measurement system using optical fibers (see top figure). This enabled us, for the first time in the world, to successfully investigate the activity of a neural subtype called the indirect pathway in the striatum, region by region. By combining activity measurement with optical manipulation (optogenetics), we discovered hidden functions for each subtype. In the behavior of mice obtaining food, the lateral indirect pathway subtype is responsible for "motivation," while the medial indirect pathway subtype is responsible for "fickleness." We also found that to turn motivation into results, it is necessary to continuously suppress this fickleness (see bottom figure).
(Kenji Tanaka, Department of Neuropsychiatry, class of '76)
2: SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters.
Nat Genet.
Nakayama RT, Pulice JL, Valencia AM, McBride MJ, McKenzie ZM, Gillespie MA, Ku WL, Teng M, Cui K, Williams RT, Cassel SH, Qing H, Widmer CJ, Demetri GD, Irizarry RA, Zhao K, Ranish JA, Kadoch C
This study is a functional analysis of the tumor suppressor gene SMARCB1 (protein name: BAF47). BAF47 is a major subunit of the hSWI/SNF (BAF) complex, which remodels chromatin in an ATP-dependent manner and regulates gene expression. Its inactivation has been reported in several refractory malignant tumors, such as malignant rhabdoid tumors. We hypothesized that "the functional abnormality of the mutant BAF complex lacking BAF47 contributes to the carcinogenesis of SMARCB1-deficient tumors." Using a very simple experimental system where we "introduce BAF47 into SMARCB1-deficient malignant tumor cell lines and observe changes in the composition and function of the BAF complex," we performed a functional analysis of BAF47. As a result, we found that the forced expression of BAF47 causes the BAF complex to bind more strongly to chromatin, broadly activating enhancers while simultaneously activating bivalent promoters that control differentiation, thereby dynamically regulating gene expression. We hope that the results of this research will contribute to elucidating the pathology not only of SMARCB1-deficient malignant tumors but also of many other refractory diseases involving mutant BAF complexes.
(Robert Nakayama, Department of Orthopedic Surgery, class of '80)
3: RNA-binding protein Qki5 regulates embryonic neural stem cells through pre-mRNA processing in cell adhesion signaling
Genes Dev.
Yoshika Hayakawa-Yano, Satoshi Suyama, Masahiro Nogami,Masato Yugami, Ikuko Koya, Takako Furukawa, Li Zhou, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi, Atsushi Nakanishi, Hideyuki Okano and Masato Yano
We have been conducting functional analyses of RNA-binding proteins involved in the development and diseases of the nervous system. As a research method, by combining HITS-CLIP analysis—a technology that snapshots protein-RNA interactions within living cells—with transcriptome analysis in an integrated multi-omics approach, and by leveraging genetic techniques, we aim to identify RNA switches that define physiological functions and to elucidate the pathology of diseases associated with RNA metabolism. In this study, we identified the RNA-binding protein Qki5, which is expressed locally in neural stem cells in the embryonic cerebral cortex. We determined the Qki5-binding RNA sites in the embryonic mouse brain at single-nucleotide resolution across the transcriptome and clarified the principles of alternative splicing control through three modes. Furthermore, using conditional knockout mice, we discovered that Qki5 regulates the β-catenin signal, which is involved in maintaining the function of embryonic neural stem cells, via multiple RNA switches. This research strategy is also useful for elucidating the pathology of various RNA-related diseases and is expected to lead to the development of new drugs for a wide range of psychiatric and neurological disorders, as well as cancer.
(Hideyuki Okano, class of '62; Masato Yano, equivalent to class of '78; Yoshika Hayakawa-Yano)