1: Structural basis for integration of GluD receptors within synaptic organizer complexes.
Science of the Month - August 2016
Science.
Jonathan Elegheert, Wataru Kakegawa, Jordan E. Clay, Natalie F. Shanks, Ester Behiels, Keiko Matsuda, Kazuhisa Kohda, Eriko Miura, Maxim Rossmann, Nikolaos Mitakidis, Junko Motohashi, Veronica T. Chang, Christian Siebold, Ingo H. Greger, Terunaga Nakagawa, Michisuke Yuzaki,* A. Radu Aricescu* (*: co-corresponding authors)
In recent years, the concept of "synaptopathies" has been proposed, suggesting that various psychiatric disorders are caused by synaptic dysfunction. In excitatory synapses, not only is the neurotransmitter glutamate released, but also a group of molecules similar to the immune system's "complement" (complement family molecules). Our laboratory has previously reported that C1ql2 and C1ql3, released from hippocampal synapses, and Cbln1, released from cerebellar synapses, simultaneously bind to postsynaptic glutamate receptors and presynaptic Neurexin to form a ternary complex. In this study, through a collaboration with Dr. Aricescu of the University of Oxford, UK, we have elucidated for the first time the three-dimensional structure of the ternary complex consisting of Neurexin-Cbln1-delta-2 glutamate receptor. The results revealed that Cbln1 acts as an "adhesive" that links the presynaptic and postsynaptic terminals, not only forming and maintaining synapses but also regulating the function of postsynaptic glutamate receptors themselves to control memory and learning processes (see figure). Such ternary complexes exist as synaptic bridges in brain regions other than the cerebellum as well. Therefore, these findings are expected to deepen our understanding of the universal synaptic control mechanisms of complement family molecules working in all brain regions and to lead to the development of new therapeutic strategies for synaptopathies.
(Wataru Kakegawa, Class of 1976 equivalent, Yuzaki Laboratory, Department of Physiology, School of Medicine)
2: Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma.
Nature.
2016 Jun 6;534(7607):407-11. doi: 10.1038/nature17988.
Fox Raymond G., Lytle Nikki K., Jaquish Dawn V., Park Frederick D., Ito Takahiro, Bajaj Jeevisha, Koechlein Claire S., Zimdahl Bryan, Yano Masato, Kopp Janel L., Kritzik Marcie, Sicklick Jason K., Sander Maike, Grandgenett Paul M., Hollingsworth Michael A., Shibata Shinsuke, Pizzo Donald, Valasek Mark A., Sasik Roman, Scadeng Miriam, Okano Hideyuki, Kim Youngsoo, MacLeod A. Robert, Lowy Andrew M., Reya
This Nature paper is the result of a joint research project between the Okano Laboratory, Department of Physiology (Shinsuke Shibata, Masato Yano (currently at Niigata University), and Hideyuki Okano) and Dr. Tannishtha Reya of UC San Diego, who is renowned for her research on cancer stem cells. In this paper, we demonstrated that Musashi1 and Musashi2, RNA-binding proteins identified by Okano and his team more than 20 years ago and responsible for stem cell self-renewal, both play a crucial role in the development of pancreatic cancer. By using a GFP reporter to visualize Musashi1 and Musashi2, we were able to visualize and isolate pancreatic cancer stem cells, revealing that Musashi-positive cells are cancer stem cells resistant to the anticancer drug gemcitabine. Furthermore, when a transgenic mouse model that develops pancreatic cancer was crossed with Musashi1 knockout mice created in the Okano Laboratory, the pancreatic cancer regressed, indicating that Musashi actively induces the properties of cancer stem cells. Additionally, using a method called HITS-CLIP, the Okano Laboratory identified the mRNAs of the HGF receptor c-MET and BRD4 and HMGA2, which are involved in epigenetic gene expression regulation, as RNA molecules that Musashi1 binds to within pancreatic cancer cells. BRD4 is a molecule that is also a molecular target for anticancer drugs, and it was thought that abnormal expression of genes related to cell carcinogenesis causes the cancerization of Musashi1-high-expressing cells. The development of anticancer drugs targeting Musashi1 is anticipated in the future.
(Hideyuki Okano, 65th class, Department of Physiology)
Other Publications
1: Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice.
Brain.
Gen Shiihashi, Daisuke Ito, Takuya Yagi, Yoshihiro Nihei, Taeko Ebine, Norihiro Suzuki
2: Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in Human Oocytes.
CELL STEM CELL,
18 (6):749-754; 10.1016/j.stem.2016.04.001 JUN 2 2016
Yamada Mitsutoshi, Emmanuele Valentina, Sanchez-Quintero Maria J., Sun Bruce, Lallos Gregory, Paull Daniel, Zimmer Matthew, Pagett Shardonay, Prosser Robert W., Sauer Mark V., Hirano Michio, Egli Dieter
3: A Colorectal Tumor Organoid Library Demonstrates Progressive Loss of Niche Factor Requirements during Tumorigenesis.
CELL STEM CELL ,
18 (6):827-838; 10.1016/j.stem.2016.04.003 JUN 2 2016
Fujii Masayuki, Shimokawa Mariko, Date Shoichi, Takano Ai, Matano Mami, Nanki Kosaku, Ohta Yuki, Toshimitsu Kohta, Nakazato Yoshihiro, Kawasaki Kenta, Uraoka Toshio, Watanabe Toshiaki, Kanai Takanori, Sato Toshiro