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Understanding ubiquitination in neurodevelopment by integrating insights across space and time

Nature Structural & Molecular Biology volume 32, pages 14–22 (2025)Cite this article

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Abstract

Ubiquitination regulates a myriad of eukaryotic signaling cascades by modifying substrate proteins, thereby determining their functions and fates. In this perspective, we discuss current challenges in investigating the ubiquitin system in the developing brain. We foster the concept that ubiquitination pathways are spatiotemporally regulated and tightly intertwined with molecular and cellular transitions during neurogenesis and neural circuit assembly. Focusing on the neurologically highly relevant class of homologous to E6AP C-terminus (HECT) ubiquitin ligases, we propose cross-disciplinary translational approaches bridging state-of-the-art cell biology, proteomics, biochemistry, structural biology and neuroscience to dissect ubiquitination in neurodevelopment and its specific perturbations in brain diseases. We highlight that a comprehensive understanding of ubiquitin signaling in the brain may reveal new horizons in basic neuroscience and clinical applications.

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Fig. 1: Transcriptomics-based temporal dynamics and cell type specificity of selected HECT-type E3s in the developing mouse cerebral cortex.

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The data presented in this manuscript are included within the paper and are available from the corresponding author upon request.

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Acknowledgements

M.C.A. is a scholar of the FENS-Kavli Network of Excellence and work in his lab is supported by the Fritz Thyssen Foundation (10.23.2.003MN) and the German Research Foundation (DFG; 515247130 and 536563141). S.L. acknowledges support from the Max Planck Institute for Multidisciplinary Sciences, the Max Planck Society and the SFB1565 (DFG; 469281184, P17).

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  1. Institute of Cell Biology and Neurobiology, Research Group ‘Proteostasis’, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, Berlin, Germany

    Mateusz C. Ambrozkiewicz

  2. Max Planck Institute for Multidisciplinary Sciences, Research Group ‘Ubiquitin Signaling Specificity’, Am Fassberg 11, Göttingen, Germany

    Sonja Lorenz

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  1. Mateusz C. Ambrozkiewicz
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M.C.A. and S.L. conceptualized and wrote the manuscript.

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Correspondence to Mateusz C. Ambrozkiewicz or Sonja Lorenz.

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Nature Structural & Molecular Biology thanks Bernhard Lechtenberg and Noelia Urbán for their contribution to the peer review of this work. Primary Handling Editor: Dimitris Typas, in collaboration with the Nature Structural and Molecular Biology team.

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Ambrozkiewicz, M.C., Lorenz, S. Understanding ubiquitination in neurodevelopment by integrating insights across space and time. Nat Struct Mol Biol 32, 14–22 (2025). https://doi.org/10.1038/s41594-024-01422-3

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