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開催日 2014/9/13
時間 18:10 - 19:10
会場 Room J(313+314)
Chairperson(s) 坂場 武史 / Takeshi Sakaba (同志社大学 脳科学研究科 / Doshisha University, Japan)
大槻 元 / Gen Ohtsuki (九州大学大学院医学研究院 分子生理学分野 / Department of Molecular Physiology, Graduate School of Medical Science, Kyushu University, Japan)

Transcription factor Npas4 regulates the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneurons

  • O3-J-6-3
  • 吉原 誠一 / Seiichi Yoshihara:1 高橋 弘雄 / Hiroo Takahashi:1 西村 信城 / Nobushiro Nishimura:1 木下 雅仁 / Masahito Kinoshita:1 朝比奈 諒 / Ryo Asahina:1 日比 陽子 / Yoko Furukawa-Hibi:2 永井 拓 / Taku Nagai:2 山田 清文 / Kiyofumi Yamada:2 坪井 昭夫 / Akio Tsuboi:1 
  • 1:奈良県立医科大学 / Faculty of Medicine, Nara Medical University, Nara, Japan 2:名古屋大学大学院医学系研究科医療薬学 / Dept of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Aichi, Japan 

Sensory experience regulates development in a variety of species and in various brain structures, including the retina, cortex, hippocampus and olfactory bulb (OB). Within the mammalian OB specifically, the development of dendrites in mitral/tufted cells is dependent on odor-evoked neural activity. However, little is known about the developmental role of sensory experience in the other major OB populations of GABA-releasing inhibitory interneurons, such as granule cells (GCs). Here, by in situ hybridization (ISH) screenings, we newly identified a transcription factor, neuronal Per/Arnt/Sim domain protein 4 (Npas4) gene, which is expressed in a subset of OB GCs following sensory experience. Npas4 contributes to inhibitory synapse development in hippocampal neurons by regulating the expression of activity-dependent genes (BDNF and c-fos) (Nature 455: 1198, 2008; Nature 503: 121, 2013). Based on lentiviral injection, Npas4 overexpression in newborn OB GCs increased the spine density even under sensory deprivation. Conversely, both Npas4 knockdown and knockout resulted in a significant reduction in the spine density of OB GCs. Furthermore, by chromatin immunoprecipitation-sequencing plus ISH screenings, we identified, as a novel target of Npas4, an E3 ubiquitin ligase Mdm2 gene, which is expressed at low levels in the wild-type OB but at higher levels in the Npas4-knockout OB. We revealed that Mdm2 ubiquitinates and degrades a microtubule-associated protein Dcx to reduce the dendritic spine density of OB GCs. Taken together, our findings suggest that Npas4 regulates Mdm2 expression to ubiquitinate and degrade Dcx for remodeling the dendritic spines of OB GCs after sensory experience (Yoshihara et al., Cell Reports, revised).

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