The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, China
Lu Rao
Department of Biochemistry and Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, United States
Peijun Li
The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, China
Xinglei Liu
Department of Biochemistry and Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, United States
Qi Wang
The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China
Alexander I Son
Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, United States
Mutations in the microtubule (MT)-binding protein doublecortin (DCX) or in the MT-based molecular motor dynein result in lissencephaly. However, a functional link between DCX and dynein has not been defined. Here, we demonstrate that DCX negatively regulates dynein-mediated retrograde transport in neurons from Dcx-/y or Dcx-/y;Dclk1-/- mice by reducing dynein’s association with MTs and disrupting the composition of the dynein motor complex. Previous work showed an increased binding of the adaptor protein C-Jun-amino-terminal kinase-interacting protein 3 (JIP3) to dynein in the absence of DCX. Using purified components, we demonstrate that JIP3 forms an active motor complex with dynein and its cofactor dynactin with two dyneins per complex. DCX competes with the binding of the second dynein, resulting in a velocity reduction of the complex. We conclude that DCX negatively regulates dynein-mediated retrograde transport through two critical interactions by regulating dynein binding to MTs and regulating the composition of the dynein motor complex.
