title: The XLID protein PQBP1 and the GTPase Dynamin 2 define a signaling link that orchestrates ciliary morphogenesis in postmitotic neurons.
abstract: Intellectual disability (ID) is a prevalent developmental disorder of cognition that remains incurable. Here, we report that knockdown of the X-linked ID (XLID) protein polyglutamine-binding protein 1 (PQBP1) in neurons profoundly impairs the morphogenesis of the primary cilium, including in the mouse cerebral cortex in vivo. PQBP1 is localized at the base of the neuronal cilium, and targeting its WW effector domain to the cilium stimulates ciliary morphogenesis. We also find that PQBP1 interacts with Dynamin 2 and thereby inhibits its GTPase activity. Accordingly, Dynamin 2 knockdown in neurons stimulates ciliogenesis and suppresses the PQBP1 knockdown-induced ciliary phenotype. Strikingly, a mutation of the PQBP1 WW domain that causes XLID disrupts its ability to interact with and inhibit Dynamin 2 and to induce neuronal ciliogenesis. These findings define PQBP1 and Dynamin 2 as components of a signaling pathway that orchestrates neuronal ciliary morphogenesis in the brain.
authors.affiliation: Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yoshiho
authors.initials: Y
authors.lastname: Ikeuchi
authors.forename: Luis
authors.initials: L
authors.lastname: de la Torre-Ubieta
authors.forename: Takahiko
authors.initials: T
authors.lastname: Matsuda
authors.forename: Hanno
authors.initials: H
authors.lastname: Steen
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa
authors.forename: Azad
authors.initials: A
authors.lastname: Bonni
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D034285:Dynamin II / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008938:Mitosis / Q000502:physiology; D009024:Morphogenesis / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C492272:Pqbp1 protein, mouse; D034285:Dynamin II