Abstract
Lissencephaly (‘smooth brain’) is a severe brain disease associated with numerous symptoms, including cognitive impairment, and shortened lifespan. The main causative gene of this disease – lissencephaly-1 (LIS1) – has been a focus of intense scrutiny since its first identification almost 30 years ago. LIS1 is a critical regulator of the microtubule motor cytoplasmic dynein, which transports numerous cargoes throughout the cell, and is a key effector of nuclear and neuronal transport during brain development. Here, we review the role of LIS1 in cellular dynein function and discuss recent key findings that have revealed a new mechanism by which this molecule influences dynein-mediated transport. In addition to reconciling prior observations with this new model for LIS1 function, we also discuss phylogenetic data that suggest that LIS1 may have coevolved with an autoinhibitory mode of cytoplasmic dynein regulation.
Highlights
Present address: †Department of Pathology and Cell Biology, Columbia University Medical Center, New York, United States
LIS1 was shown to improve the ability of DDA complexes to migrate through microtubulebound tau condensates, suggesting that LIS1 enhances the ability of dynein-dynactin complexes to overcome obstacles (Tan et al, 2019). All of these results suggest that LIS1 could conceivably modulate the force-producing properties of dynein for efficient transport of diverse cargos in a crowded cellular environment
Using single-molecule assays, they noted that addition of Pac1 increased the run length of wild-type dynein, but not ‘open’ dynein mutants, similar to some of the results reported for the mammalian homologues
Summary
As a consequence of its central roles in lissencephaly and brain development, LIS1 has been a focus of intense scrutiny ever since its discovery 27 years ago. These studies have revealed invaluable insight into the cellular and biochemical roles for this molecule in neuronal function. Given the well-defined role for the dynein complex in effecting microtubulebased transport – and in neuronal migration – the molecular basis for LIS1-related lissencephalies is likely defective dynein-based transport. We summarize the cell biological and genetic data defining the role for LIS1 in cell and organismal function, and the wealth of biochemical data that have shed invaluable light on the mechanism by which this molecule functions. In addition to describing a phylogenetic relationship between LIS1 and dynein autoinhibition, we will attempt to reconcile the numerous – and at times contradictory – biochemical findings with in vivo data to synthesize them into a coherent model for LIS1 function in the dynein pathway
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
