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.
Cell Rep. 2013 Sep 12;4(5):879-89. doi: 10.1016/j.celrep.2013.07.042. Epub 2013 Aug 29.
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.
智力障碍（ID）是一种普遍存在的认知发育障碍，目前无法治愈。在这里，我们报告说，神经元中 X 连锁智力障碍（XLID）蛋白多聚谷氨酰胺结合蛋白 1（PQBP1）的敲低会严重损害初级纤毛的形态发生，包括在体内的小鼠大脑皮层。PQBP1 位于神经元纤毛的基部，将其 WW 效应结构域靶向纤毛会刺激纤毛形态发生。我们还发现 PQBP1 与动力蛋白 2 相互作用，从而抑制其 GTPase 活性。因此，神经元中的 Dynamin 2 敲低会刺激纤毛发生，并抑制 PQBP1 敲低诱导的纤毛表型。引人注目的是，导致 XLID 的 PQBP1 WW 结构域突变会破坏其与 Dynamin 2 相互作用和抑制 Dynamin 2 的能力，并诱导神经元纤毛发生。这些发现将 PQBP1 和 Dynamin 2 定义为协调大脑中神经元纤毛形态发生的信号通路的组成部分。
