Septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation

被引:93
作者
Ageta-Ishihara, Natsumi [1 ]
Miyata, Takaki [2 ]
Ohshima, Chika [1 ]
Watanabe, Masahiko [3 ]
Sato, Yoshikatsu [4 ]
Hamamura, Yuki [1 ]
Higashiyama, Tetsuya [4 ]
Mazitschek, Ralph [5 ,6 ]
Bito, Haruhiko [7 ]
Kinoshita, Makoto [1 ]
机构
[1] Nagoya Univ, Grad Sch Sci, Div Biol Sci, Nagoya, Aichi 4648602, Japan
[2] Nagoya Univ, Grad Sch Med, Dept Anat & Cell Biol, Nagoya, Aichi 4668550, Japan
[3] Hokkaido Univ, Grad Sch Med, Dept Anat, Sapporo, Hokkaido 0608638, Japan
[4] Nagoya Univ, Inst Transformat Bio Mol, Nagoya, Aichi 4648602, Japan
[5] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA
[6] Harvard Univ, Sch Med, Boston, MA 02114 USA
[7] Univ Tokyo, Grad Sch Med, Dept Neurochem, Tokyo 1130033, Japan
来源
NATURE COMMUNICATIONS | 2013年 / 4卷
关键词
BINDING PROTEIN; MAMMALIAN SEPTINS; NEUROTRANSMITTER RELEASE; CAENORHABDITIS-ELEGANS; FLUORESCENT PROTEIN; MOUSE MODEL; HDAC6; TUBULIN; NEURONS; GROWTH;
D O I
10.1038/ncomms3532
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Neurite growth requires two guanine nucleotide-binding protein polymers of tubulins and septins. However, whether and how those cytoskeletal systems are coordinated was unknown. Here we show that the acute knockdown or knockout of the pivotal septin subunit SEPT7 from cerebrocortical neurons impairs their interhemispheric and cerebrospinal axon projections and dendritogenesis in perinatal mice, when the microtubules are severely hyperacetylated. The resulting hyperstabilization and growth retardation of microtubules are demonstrated in vitro. The phenotypic similarity between SEPT7 depletion and the pharmacological inhibition of a-tubulin deacetylase HDAC6 reveals that HDAC6 requires SEPT7 not for its enzymatic activity, but to associate with acetylated a-tubulin. These and other findings indicate that septins provide a physical scaffold for HDAC6 to achieve efficient microtubule deacetylation, thereby negatively regulating microtubule stability to an optimal level for neuritogenesis. Our findings shed light on the mechanisms underlying the HDAC6-mediated coupling of the two ubiquitous cytoskeletal systems during neural development.
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页数:11
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