Hypoxia-inducible factor-1a contributes to dendritic overgrowth in tuberous sclerosis

NEUROSCIENCE LETTERS

卷:612

Article

Zhang, Longbo^1,2,3  Feliciano, David M.^1,2  Huang, Tianxiang^1,2,3  Zhang, Shiliang^1,2  Bordeya, Angelique^1,2 

[1] Yale Univ, Sch Med, Dept Neurosurg, 333 Cedar St,FMB 422, New Haven, CT 06520 USA

[2] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, 333 Cedar St, New Haven, CT 06520 USA

[3] Cent S Univ, Xiangya Hosp, Dept Neurosurg, Changsha, Hunan, Peoples R China

关键词: Tuberous sclerosis complex;    mTOR;    HIF1;    Dendrite;    Brain development;    Cognitive disease;    Hypoxia;    Cognition;   

DOI  :  10.1016/j.neulet.2015.11.038

来源: Elsevier

【 摘 要 】

Expression of hypoxia-inducible factor 1a (HIF1a) is increased under several pathological conditions such as hyperactive mechanistic target of rapamycin complex 1 (mTORC1) in tuberous sclerosis complex (TSC). Hyperactive mTORC1 and the resulting increased dendritic complexity of neurons are shared molecular and cellular alterations in several neurological disorders associated with cognitive disabilities. Despite some evidence that HIF1a contributes to dendritic overgrowth in vitro, it remains unknown whether increased HIF1a in TSC neurons could contribute to their increased dendritic complexity. To address this use in vivo, we generated TSC neurons by deleting Tsc1 in newborn olfactory bulb (OB) neurons of conditional Tsc1 transgenic mice using neonatal electroporation. In addition to their increased dendritic complexity, Tsc1(null) neurons have been reported to display increased Hif1a mRNA level and HIF1a transcriptional activity. We found that Tsc1(null)-dependent dendritic overgrowth was prevented by knocking down HIF1a or expressing a dominant negative HIF1a. In addition, overexpressing HIF1a in wild-type developing neurons resulted in increased dendritic complexity in vivo. These data highlight that an increase in HIF1a levels contributes to abnormal dendritic patterning in developing neurons under normal conditions and hyperactive mTORC1 conditions as in TSC. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

【 授权许可】

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