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Neurosci Lett. 2016 Jan 26;612:43-47. doi: 10.1016/j.neulet.2015.11.038. Epub 2015 Dec 2.

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

Author information

1
Departments of Neurosurgery, and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520-8082 Changsha, China; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
2
Departments of Neurosurgery, and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520-8082 Changsha, China.
3
Departments of Neurosurgery, and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520-8082 Changsha, China. Electronic address: angelique.bordey@yale.edu.

Abstract

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.

KEYWORDS:

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

PMID:
26655465
PMCID:
PMC4728030
DOI:
10.1016/j.neulet.2015.11.038
[Indexed for MEDLINE]
Free PMC Article

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