title: MEK-ERK1/2-dependent FLNA overexpression promotes abnormal dendritic patterning in tuberous sclerosis independent of mTOR.
abstract: Abnormal dendritic complexity is a shared feature of many neurodevelopmental disorders associated with neurological defects. Here, we found that the actin-crosslinking protein filamin A (FLNA) is overexpressed in tuberous sclerosis complex (TSC) mice, a PI3K-mTOR model of neurodevelopmental disease that is associated with abnormal dendritic complexity. Both under- and overexpression of FLNA in wild-type neurons led to more complex dendritic arbors in vivo, suggesting that an optimal level of FLNA expression is required for normal dendritogenesis. In Tsc1(null) neurons, knocking down FLNA in vivo prevented dendritic abnormalities. Surprisingly, FLNA overexpression in Tsc1(null) neurons was dependent on MEK1/2 but not mTOR activity, despite both pathways being hyperactive. In addition, increasing MEK-ERK1/2 activity led to dendritic abnormalities via FLNA, and decreasing MEK-ERK1/2 signaling in Tsc1(null) neurons rescued dendritic defects. These data demonstrate that altered FLNA expression increases dendritic complexity and contributes to pathologic dendritic patterning in TSC in an mTOR-independent, ERK1/2-dependent manner.
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central South University, 85 Xiangya Street, Changsha, 410008, China; Department of Neurosurgery and Department of Cellular & Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: Longbo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery and Department of Cellular & Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA; Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bartley
authors.affiliation: Department of Neurosurgery, Xiangya Hospital, Central South University, 85 Xiangya Street, Changsha, 410008, China; Department of Neurosurgery and Department of Cellular & Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Gong
authors.affiliation: Department of Neurosurgery and Department of Cellular & Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Hsieh
authors.affiliation: Department of Neurosurgery and Department of Cellular & Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: Tiffany V
authors.initials: TV
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery and Department of Cellular & Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Feliciano
authors.affiliation: Department of Neurosurgery and Department of Cellular & Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8082, USA. Electronic address: angelique.bordey@yale.edu.
authors.forename: Angélique
authors.initials: A
authors.lastname: Bordey
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D045744:Cell Line, Tumor; D003712:Dendrites / Q000378:metabolism* / Q000473:pathology; D005260:Female; D064448:Filamins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009924:Organ Culture Techniques; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: C578663:FLNA protein, human; D064448:Filamins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases