title: A Cdk5-dependent switch regulates Lis1/Ndel1/dynein-driven organelle transport in adult axons.
abstract: Lissencephaly is a human developmental brain abnormality caused by LIS1 haploinsufficiency. This disorder is in large part attributed to altered mitosis and migration in the developing brain. LIS1 and an interacting protein, NDEL1, bind to cytoplasmic dynein, a microtubule motor protein. While the tripartite complex is clearly important for developmental events, we are intrigued by the fact that Lis1 and Ndel1 expression remain high in the adult mouse nervous system. Dynein plays a crucial role in retrograde axonal transport, a process that is used by mature neurons. Here, we monitored acidic organelles moving in axons of adult rat sensory neurons to determine whether Lis1 and Ndel1 contribute to axonal transport. Lis1 RNAi significantly reduced axon transport of these organelles. Ndel1 RNAi had little impact, but combined Lis1 and Ndel1 RNAi caused a more severe phenotype than Lis1 RNAi alone, essentially shutting down transport. Lis1 overexpression stimulated retrograde transport, while a Lis1 dynein-binding mutant severely disrupted transport. Overexpression of Ndel1 or a Lis1 Ndel1-binding mutant only mildly perturbed transport. However, expressing a mutant Ndel1 lacking key phosphorylation sites shut down transport completely, as did a dominant-negative Cdk5 construct. We propose that, in axons, unphosphorylated Ndel1 inhibits the capacity of dynein to transport acidic organelles. Phosphorylation of Ndel1 by Cdk5 not only reduces this inhibition but also allows Lis1 to further stimulate the cargo transport capacity of dynein. Our data raise the possibility that defects in a Lis1/Ndel1 regulatory switch could contribute to neurodegenerative diseases linked to axonal pathology in adults.
authors: Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208, USA.
authors: Jai P
authors: JP
authors: Pandey
authors: Deanna S
authors: DS
authors: Smith
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000502:physiology; D001692:Biological Transport / Q000502:physiology; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D004398:Dyneins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D015388:Organelles / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; C486015:Ndel1 protein, mouse; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse; D004398:Dyneins