Electron cryo-tomography reveals the subcellular architecture of growing axons in human brain organoids

Author:

Hoffmann Patrick C1ORCID,Giandomenico Stefano L1ORCID,Ganeva Iva1ORCID,Wozny Michael R1ORCID,Sutcliffe Magdalena1ORCID,Lancaster Madeline A1ORCID,Kukulski Wanda12ORCID

Affiliation:

1. MRC Laboratory of Molecular Biology, Francis Crick Avenue

2. Institute of Biochemistry and Molecular Medicine, University of Bern

Abstract

During brain development, axons must extend over great distances in a relatively short amount of time. How the subcellular architecture of the growing axon sustains the requirements for such rapid build-up of cellular constituents has remained elusive. Human axons have been particularly poorly accessible to imaging at high resolution in a near-native context. Here, we present a method that combines cryo-correlative light microscopy and electron tomography with human cerebral organoid technology to visualize growing axon tracts. Our data reveal a wealth of structural details on the arrangement of macromolecules, cytoskeletal components, and organelles in elongating axon shafts. In particular, the intricate shape of the endoplasmic reticulum is consistent with its role in fulfilling the high demand for lipid biosynthesis to support growth. Furthermore, the scarcity of ribosomes within the growing shaft suggests limited translational competence during expansion of this compartment. These findings establish our approach as a powerful resource for investigating the ultrastructure of defined neuronal compartments.

Funder

Medical Research Council

European Research Council

Natural Sciences and Engineering Research Council of Canada

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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