title: Hypoxia-inducible factor-1a contributes to dendritic overgrowth in tuberous sclerosis.
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.
authors.affiliation: 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.
authors.forename: Longbo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Departments of Neurosurgery, and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520-8082 Changsha, China.
authors.forename: David M
authors.initials: DM
authors.lastname: Feliciano
authors.affiliation: 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.
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Huang
authors.affiliation: Departments of Neurosurgery, and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520-8082 Changsha, China.
authors.forename: Shiliang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Angélique
authors.initials: A
authors.lastname: Bordey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003712:Dendrites / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D014402:Tuberous Sclerosis / Q000378:metabolism* / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins
keywords: Brain development; Cognition; Cognitive disease; Dendrite; HIF1; Hypoxia; Tuberous sclerosis complex; mTOR