Research & Publications
Neurons are among the largest, most polarized cells in our bodies. The ability to maintain the local protein and organelle composition remotely from the cell body at precise locations such as synapses is crucial for neurons to receive and propagate information.
The lab is interested in the cell biological mechanisms that generate the polarized distribution of organelles in axons and dendrites through long-range transport on microtubule tracks. We would like to understand the formation and patterning of the neuronal microtubule network, and how its architecture and dynamic properties regulate cargo transport.
We combine live-imaging, custom image analysis tools, genetics and cell biological approaches to study these questions with single-cell resolution using the nervous system of C. elegans as a model. With this approach we aim to generate new insights into the formation and function of the neuronal cytoskeleton, which would also help us to understand its dysfunction during aging or in diseases such as Taupathies.
Extensive Research Description
Neurons are among the largest, most polarized cells in our bodies. The ability to precisely deliver cellular organelles such as synaptic vesicles or RNA particles to remote locations in axons and dendrites is fundamental for neurons to efficiently receive and propagate information. This long-range transport is carried out by molecular motors moving on cytoskeletal tracks, and is crucial for maintaining the composition of synapses over the lifetime of a neuron.
We are interested in the cell biological mechanisms that neurons employ to establish microtubule tracks and maintain the distribution of their organelles via polarized cargo transport. For example:
-How are microtubule tracks nucleated and patterned in axons and dendrites? How are their length, number and orientation optimized for transport in different neurons?
-How do molecular motors navigate their way on microtubule tracks to pick up and unload cargo at precise locations?
-What are the cues that determine the steady state localization of cargo such as RNA particles?
We established imaging and image analysis tools that allow us to study the organization of the cytoskeleton and overlying transport of cargo in live animals with high resolution in single cells. We use the nematode C. elegans for these studies because of its transparent body and its amenability to forward genetic approaches. The conservation of the basic cellular machinery between C. elegans and mammalian neurons allows us to use this simple model to gain insight into fundamental processes that occur in neurons of higher organisms. Because defective microtubule dependent transport is a hallmark of neurodegeneration, we hope that these insights will also help us understand the relevant mechanisms of cellular dysfunction.
Axonal Transport; Cell Biology; Cytoskeleton; Neurons; Synapses; Motor Neuron Disease
- Distinguishing synaptic vesicle precursor navigation of microtubule ends with a single rate constant modelGramlich M, Balseiro-Gómez S, Tabei S, Parkes M, Yogev S. Distinguishing synaptic vesicle precursor navigation of microtubule ends with a single rate constant model Scientific Reports 2021, 11: 3444. PMID: 33564025, PMCID: PMC7873188, DOI: 10.1038/s41598-021-82836-7.
- Local inhibition of microtubule dynamics by dynein is required for neuronal cargo distributionYogev S, Maeder CI, Cooper R, Horowitz M, Hendricks AG, Shen K. Local inhibition of microtubule dynamics by dynein is required for neuronal cargo distribution Nature Communications 2017, 8: 15063. PMID: 28406181, PMCID: PMC5399302, DOI: 10.1038/ncomms15063.
- Microtubule Organization Determines Axonal Transport DynamicsYogev S, Cooper R, Fetter R, Horowitz M, Shen K. Microtubule Organization Determines Axonal Transport Dynamics Neuron 2016, 92: 449-460. PMID: 27764672, PMCID: PMC5432135, DOI: 10.1016/j.neuron.2016.09.036.
- Cellular and Molecular Mechanisms of Synaptic SpecificityYogev S, Shen K. Cellular and Molecular Mechanisms of Synaptic Specificity Annual Review Of Cell And Developmental Biology 2014, 30: 1-21. PMID: 25150010, DOI: 10.1146/annurev-cellbio-100913-012953.
- Generation of distinct signaling modes via diversification of the Egfr ligand-processing cassetteRousso T, Lynch J, Yogev S, Roth S, Schejter E, Shilo B. Generation of distinct signaling modes via diversification of the Egfr ligand-processing cassette Journal Of Cell Science 2010, 123: e1-e1. DOI: 10.1242/jcs.081646.
- Polarized Secretion of Drosophila EGFR Ligand from Photoreceptor Neurons Is Controlled by ER Localization of the Ligand-Processing MachineryYogev S, Schejter ED, Shilo BZ. Polarized Secretion of Drosophila EGFR Ligand from Photoreceptor Neurons Is Controlled by ER Localization of the Ligand-Processing Machinery PLOS Biology 2010, 8: e1000505. PMID: 20957186, PMCID: PMC2950126, DOI: 10.1371/journal.pbio.1000505.
- Drosophila EGFR signalling is modulated by differential compartmentalization of Rhomboid intramembrane proteasesYogev S, Schejter ED, Shilo B. Drosophila EGFR signalling is modulated by differential compartmentalization of Rhomboid intramembrane proteases The EMBO Journal 2008, 27: 1219-1230. PMID: 18369317, PMCID: PMC2367402, DOI: 10.1038/emboj.2008.58.