Doublecortin and JIP3 are neural-specific counteracting regulators of dynein-mediated retrograde trafficking.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36476638.
- Also identified by DOI 10.7554/eLife.82218 and PMC identifier 9799976.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 <i>Dcx<sup>-/y</sup></i> or <i>Dcx<sup>-/y</sup>;Dclk1<sup>-/-</sup></i> 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.
Medical subject headings
- Dyneins
- Microtubules