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J. Biol. Chem., Vol. 282, Issue 47, 34525-34534, November 23, 2007

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The Role of Brain-derived Neurotrophic Factor (BDNF)-induced XBP1 Splicing during Brain Development^*

Akiko Hayashi, Takaoki Kasahara, Kazuya Iwamoto, Mizuho Ishiwata, Mizue Kametani, Chihiro Kakiuchi, Teiichi Furuichi, and Tadafumi Kato¹

From the Laboratory for Molecular Dynamics of Mental Disorders and the Laboratory for Molecular Neurogenesis, Brain Science Institute, RIKEN, Wako 351-0198, Japan

Accumulation of unfolded proteins in the endoplasmic reticulum initiates intracellular signaling termed the unfolded protein response (UPR). Although Xbp1 serves as a pivotal transcription factor for the UPR, the physiological role of UPR signaling and Xbp1 in the central nervous system remains to be elucidated. Here, we show that Xbp1 mRNA was highly expressed during neurodevelopment and activated Xbp1 protein was distributed throughout developing neurons, including neurites. The isolated neurite culture system and time-lapse imaging demonstrated that Xbp1 was activated in neurites in response to brain-derived neurotrophic factor (BDNF), followed by subsequent translocation of the active Xbp1 into the nucleus. BDNF-dependent neurite outgrowth was significantly attenuated in Xbp1^-/- neurons. These findings suggest that BDNF initiates UPR signaling in neurites and that Xbp1, which is activated as part of the UPR, conveys the local information from neurites to the nucleus, contributing the neurite outgrowth.

Received for publication, May 24, 2007 , and in revised form, September 17, 2007.

^* This work was supported in part by grants to the Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, a grant-in-aid from the Japanese Ministry of Health and Labor, and a grant-in-aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S6, Table S1, and Video S1.

¹ To whom correspondence should be addressed: Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan. Tel.: 81-48-467-6949; Fax: 81-48-467-6947; E-mail: kato{at}brain.riken.jp.

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