Differential roles of NF-Y transcription factor in ER chaperone expression and neuronal maintenance in the CNS.
The mammalian central nervous system (CNS) contains various types of neurons with different neuronal functions. In contrast to established roles of cell type-specific transcription factors on neuronal specification and maintenance, whether ubiquitous transcription factors have conserved or differential neuronal function remains uncertain. Here, we revealed that inactivation of a ubiquitous factor NF-Y in different sets of neurons resulted in cell type-specific neuropathologies and gene downregulation in mouse CNS. In striatal and cerebellar neurons, NF-Y inactivation led to ubiquitin/p62 pathologies with downregulation of an endoplasmic reticulum (ER) chaperone Grp94, as we previously observed by NF-Y deletion in cortical neurons. In contrast, NF-Y inactivation in motor neurons induced neuronal loss without obvious protein deposition. Detailed analysis clarified downregulation of another ER chaperone Grp78 in addition to Grp94 in motor neurons, and knockdown of both ER chaperones in motor neurons recapitulated the pathology observed after NF-Y inactivation. Finally, additional downregulation of Grp78 in striatal neurons suppressed ubiquitin accumulation induced by NF-Y inactivation, implying that selective ER chaperone downregulation mediates different neuropathologies. Our data suggest distinct roles of NF-Y in protein homeostasis and neuronal maintenance in the CNS by differential regulation of ER chaperone expression.
Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science, Kyoto 610-0394, Japan.|Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan.|Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.|Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Tomoyuki
T
Yamanaka
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Asako
A
Tosaki
Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science, Kyoto 610-0394, Japan.|Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan.|Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.|Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Haruko
H
Miyazaki
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan.|Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
Masaru
M
Kurosawa
Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
Masato
M
Koike
Departments of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
Yasuo
Y
Uchiyama
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Sankar N
SN
Maity
Division of Pharmacology, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
Hidemi
H
Misawa
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Ryosuke
R
Takahashi
Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Tomomi
T
Shimogori
Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
Nobutaka
N
Hattori
Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science, Kyoto 610-0394, Japan.|Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan.|Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.|Laboratory for Molecular Mechanisms of Thalamus Development, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Nobuyuki
N
Nukina
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