IAS Distinguished Lecture - Keeping Neurons in Shape: Roles for Phospholipid Asymmetry and Extracellular Vesicles

Abstract

The functioning of the brain relies on the stability of its component neurons, which can maintain their morphology for extended periods in adult life. Compared to early developmental neurite outgrowth or axon guidance, less is known about how mature neurons maintain their shapes. The speaker and his research team use the C. elegans animal model to dissect genetic pathways that maintain neuronal morphology. Loss of function mutations in a conserved lipid metabolism regulator result in failure to maintain neuronal morphology and enhanced axon regeneration after axon injury. These mutants strongly synergize with loss of function in a signaling scaffold protein such that double mutants display severe defects in neuronal morphology maintenance and elevated release of neuronal extracellular vesicles (EVs). Using genetic screening for suppressors of these phenotypes we identified multiple gainof-function mutations affecting a phospholipid flippase and its regulator that can restore normal neuronal morphology and suppress EV release. These gain-of-function mutations define novel protein domains with regulatory functions. Their studies reveal critical roles for phospholipid asymmetry and regulation of EV release in maintaining morphology of neurons and other cell types. Notably, human orthologs of all these proteins have been implicated in a variety of neurodevelopmental and neurodegenerative disorders.


About the Speaker

Prof. Andrew CHISHOLM received his PhD in 1989 from the University of Cambridge, working at the MRC Laboratory of Molecular Biology. He did postdoctoral research with Prof. H. Robert HORVITZ at the Massachusetts Institute of Technology where he held a Lucille P. Markey postdoctoral fellowship. He was on the faculty of the University of California, Santa Cruz where he rose to the rank of Professor before moving to University of California, San Diego (UCSD) in 2007. From 2016-2019, he was Head of Cellular and Developmental Sciences at the Wellcome Trust in London. Then he was appointed as Associate Dean of the Division of Biological Sciences at UCSD. He is currently Distinguished Professor of Neurobiology and of Cell and Developmental Biology at UCSD.