The role of brain-derived neurotrophic factor (BDNF)-induced XBP1 splicing during brain development.
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.
Hayashi
Akiko
A
Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute RIKEN, Hirosawa, Wako-shi, Saitama, Japan.
Kasahara
Takaoki
T
Iwamoto
Kazuya
K
Ishiwata
Mizuho
M
Kametani
Mizue
M
Kakiuchi
Chihiro
C
Furuichi
Teiichi
T
Kato
Tadafumi
T
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001921:Brain / Q000196:embryology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016501:Neurites / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D012326:RNA Splicing / Q000502:physiology*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1
D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse