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The role of ubiquitylation in nerve cell development

Nature Reviews Neuroscience volume 12, pages 251–268 (2011)Cite this article

Subjects

Key Points

  • Ubiquitylation is emerging as a general regulatory mechanism in nerve cell development, on a par with phosphorylation or cyclic nucleotide signalling with regard to complexity and functional consequences.

  • The currently available evidence is still restricted to a limited set of example pathways, but these examples provide an exciting view of how ubiquitylation-dependent regulatory processes in neurons intercalate with other, more extensively studied regulatory principles to control all phases of nerve cell development: the generation of neurons from precursor cells, their migration to the appropriate target sites, their extensive arborization and their integration into functional networks through synapse formation. Currently, we see only the tip of the iceberg.

  • Notch-mediated regulation of neurogenesis and gliogenesis is controlled directly and indirectly by multiple ubiquitylation pathways.

  • Polyubiquitylation and degradation of disabled homologue 1 (DAB1) — an adaptor protein for reelin receptors, very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor type 2 (APOER2) — is crucial for neuronal migration in the cortex by throttling reelin signalling.

  • Signalling pathways controlling neurite development and axon acquisition are controlled by specific monoubiquitylation, diubiquitylation or polyubiquitylation of small GTPases. Typically, these types of ubiquitylation negatively regulate GTPase function or expression.

  • The RING finger E3 ligases RPM1 (also known as highwire) and the SCF complex function in synaptogenesis and synapse elimination by polyubiquitylating target proteins at synaptic or extrasynaptic locations in axons. Spatial restriction of ubiquitylation is essential for synapse elimination.

Abstract

Nerve cell development in the brain is a tightly regulated process. The generation of neurons from precursor cells, their migration to the appropriate target sites, their extensive arborization and their integration into functional networks through synapse formation and refinement are governed by multiple interdependent signalling cascades. The function and turnover of proteins involved in these signalling cascades, in turn, are spatially and temporally controlled by ubiquitylation. Recent advances have provided first insights into the highly complex and intricate molecular pathways that regulate ubiquitylation during all stages of neural development and that operate in parallel with other regulatory processes such as phosphorylation or cyclic nucleotide signalling.

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Figure 1: Key steps of neuronal differentiation in the mammalian brain.
Figure 2: The protein ubiquitylation pathway.
Figure 3: Regulation of neurogenesis by ubiquitylation.
Figure 4: Molecular pathways in reelin signalling.
Figure 5: Regulation of neuritogenesis by ubiquitylation.
Figure 6: Regulation of synaptogenesis by PHR family ligases.

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Acknowledgements

We thank J. Stegmüller for helpful discussions and comments on this manuscript. Work in the authors' laboratories was supported by grants from the Max Planck Society (to N.B.), the German Research Foundation (SFB271/B11 to N.B.), the European Commission (EUSynapse, EUROSPIN and SynSys to N.B) and the Fritz Thyssen Foundation (to H.K.).

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  1. Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Hermann-Rein Straße 3, D-37075, Göttingen, Germany

    Hiroshi Kawabe & Nils Brose

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Kawabe, H., Brose, N. The role of ubiquitylation in nerve cell development. Nat Rev Neurosci 12, 251–268 (2011). https://doi.org/10.1038/nrn3009

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