Key Points
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Rho GTPases have been extensively studied in fibroblasts, where their role in the regulation of actin dynamics is well understood. As there are notable similarities between actin-based structures in fibroblasts and neuronal growth cones, the study of Rho GTPases in the context of the neuronal cytoskeleton has gained a lot of recent attention.
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Many cellular processes during neuron development involve the regulation of the cytoskeleton in response to extracellular cues. In this review, the function of Rho GTPases in five aspects of neuronal morphogenesis is discussed: neuronal migration, establishment of neuronal polarity, axon growth and guidance, dendritic development and plasticity, and synapse development. Emphasis is placed on the sections relating to axons and dendrites, as more studies have been conducted in these two areas.
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The signal-transduction pathways known or thought to mediate the effects of Rho GTPases are discussed. First, the role of extracellular cues in the regulation of Rho GTPase activity is considered. The mechanisms whereby Rho GTPases send signals to regulate different aspects of actin cytoskeleton dynamics are then described.
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Several human genetic mutations in components of Rho GTPase signalling pathways have been identified. Some of them affect primarily the nervous system and the best characterized of these are briefly discussed.
Abstract
The Rho family of small GTPases act as intracellular molecular switches that transduce signals from extracellular stimuli to the actin cytoskeleton and the nucleus. Recent evidence implicates Rho GTPases in the regulation of neuronal morphogenesis, including migration, polarity, axon growth and guidance, dendrite elaboration and plasticity, and synapse formation. Signalling pathways from membrane receptors to Rho GTPases and from Rho GTPases to the actin cytoskeleton are beginning to be discovered. Mutations in these signalling pathways have been reported in human neurological diseases, which underscores their importance in the development and function of the nervous system.
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Acknowledgements
I thank all members of my lab, in particular P. Billuart and A. Y. N. Goldstein, as well as many colleagues in the field, for their contributions to the idea and work described here. I also thank many lab members and J. Goldberg for helpful comments on the manuscript. Work in the lab was supported by grants from the NIH, the MDA, and the McKnight, Klingenstein and Sloan foundations.
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Glossary
- CONSTITUTIVELY ACTIVE
-
Mutant proteins that remain active in the absence of upstream signals. In the case of Rho GTPases, common constitutively active mutants act by inhibiting the GTPase activity, thereby preventing them from being `switched off'.
- DOMINANT-NEGATIVE
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Non-functional mutant proteins that interfere with the functions of the endogenous wild-type proteins. In the case of Rho GTPases, common dominant-negative mutants act by titrating guanine nucleotide exchange factors. The specificity of a dominant-negative mutant therefore relies on targeting the factor(s) that are specific for the GTPase of interest.
- STRESS FIBRES
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Axial bundles of F-actin underlying the cell bodies.
- LAMELLIPODIA
-
Structures at the edge of cells composed of a crosslinked F-actin meshwork.
- FILOPODIA
-
Long, thin protrusions at the periphery of cells and growth cones. They are composed of F-actin bundles.
- CYTOKINESIS
-
The division of cytoplasm of a parent cell after nuclear division.
- SH2 DOMAIN
-
(Src-homology region 2). Protein sequence of about 100 amino acids found in many proteins involved in signal transduction.
- SH3 DOMAIN
-
(Src-homology region 3). Protein sequence of about 50 amino acids that recognizes and binds to sequences rich in proline.
- PLECKSTRIN-HOMOLOGY DOMAIN
-
A sequences of about 100 amino acids present in many signalling molecules. Pleckstrin is a protein of unknown function originally identified in platelets. It is a principal substrate of protein kinase C.
- PDZ DOMAIN
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(Postsynaptic density-95, Discs-large, Zona occludens-1). Protein–protein interaction domain.
- EFFECTORS
-
Proteins that bind to Rho GTPases only when they are in an active GTP-bound state and are therefore likely to transduce signals downstream of the Rho GTPases.
- LOSS-OF-FUNCTION MUTATION
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Mutation that causes a decrease or the total loss of the activity of the encoded protein. Although genetic loss-of-function mutants provide the most rigorous test for the function of genes, mutations in Rho GTPases are likely to cause pleiotropic defects. Conditional knockouts in small populations of neurons might provide more useful information.
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Luo, L. RHO GTPASES in neuronal morphogenesis. Nat Rev Neurosci 1, 173–180 (2000). https://doi.org/10.1038/35044547
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DOI: https://doi.org/10.1038/35044547
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