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Featured ArticleResearch Articles, Cellular/Molecular

Tuba Activates Cdc42 during Neuronal Polarization Downstream of the Small GTPase Rab8a

Pamela J. Urrutia, Felipe Bodaleo, Daniel A. Bórquez, Yuta Homma, Victoria Rozes-Salvador, Cristopher Villablanca, Cecilia Conde, Mitsunori Fukuda and Christian González-Billault
Journal of Neuroscience 24 February 2021, 41 (8) 1636-1649; DOI: https://doi.org/10.1523/JNEUROSCI.0633-20.2020
Pamela J. Urrutia
1Laboratory of Cell and Neuronal Dynamics, Department of Biology, Faculty of Sciences, Universidad de Chile, 7800003, Santiago, Chile
3Geroscience Center for Brain Health and Metabolism, 7800003, Santiago, Chile
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Felipe Bodaleo
1Laboratory of Cell and Neuronal Dynamics, Department of Biology, Faculty of Sciences, Universidad de Chile, 7800003, Santiago, Chile
3Geroscience Center for Brain Health and Metabolism, 7800003, Santiago, Chile
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  • ORCID record for Felipe Bodaleo
Daniel A. Bórquez
4Laboratory of Signalling and Bioinformatics, Faculty of Medicine, Universidad Diego Portales, 8370007, Santiago, Chile
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Yuta Homma
6Laboratory of Membrane Trafficking Mechanisms, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, 980-8577, Sendai, Japan
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Victoria Rozes-Salvador
5Instituto de Investigación Médica Mercedes y Martin Ferreyra, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, X5016NST, Córdoba, Argentina
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Cristopher Villablanca
1Laboratory of Cell and Neuronal Dynamics, Department of Biology, Faculty of Sciences, Universidad de Chile, 7800003, Santiago, Chile
3Geroscience Center for Brain Health and Metabolism, 7800003, Santiago, Chile
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Cecilia Conde
5Instituto de Investigación Médica Mercedes y Martin Ferreyra, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, X5016NST, Córdoba, Argentina
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Mitsunori Fukuda
6Laboratory of Membrane Trafficking Mechanisms, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, 980-8577, Sendai, Japan
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Christian González-Billault
1Laboratory of Cell and Neuronal Dynamics, Department of Biology, Faculty of Sciences, Universidad de Chile, 7800003, Santiago, Chile
2Department of Neuroscience, Faculty of Medicine, Universidad de Chile, 8380447, Santiago, Chile
3Geroscience Center for Brain Health and Metabolism, 7800003, Santiago, Chile
7The Buck Institute for Research on Aging, 94945, Novato
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Abstract

The acquisition of neuronal polarity is a complex molecular process that depends on changes in cytoskeletal dynamics and directed membrane traffic, regulated by the Rho and Rab families of small GTPases, respectively. However, during axon specification, a molecular link that couples these protein families has yet to be identified. In this paper, we describe a new positive feedback loop between Rab8a and Cdc42, coupled by Tuba, a Cdc42-specific guanine nucleotide-exchange factor (GEF), that ensures a single axon generation in rodent hippocampal neurons from embryos of either sex. Accordingly, Rab8a or Tuba gain-of-function generates neurons with supernumerary axons whereas Rab8a or Tuba loss-of-function abrogated axon specification, phenocopying the well-established effect of Cdc42 on neuronal polarity. Although Rab8 and Tuba do not interact physically, the activity of Rab8 is essential to generate a proximal to distal axonal gradient of Tuba in cultured neurons. Tuba-associated and Rab8a-associated polarity defects are also evidenced in vivo, since dominant negative (DN) Rab8a or Tuba knock-down impairs cortical neuronal migration in mice. Our results suggest that Tuba coordinates directed vesicular traffic and cytoskeleton dynamics during neuronal polarization.

SIGNIFICANCE STATEMENT The morphologic, biochemical, and functional differences observed between axon and dendrites, require dramatic structural changes. The extension of an axon that is 1 µm in diameter and grows at rates of up to 500 µm/d, demands the confluence of two cellular processes: directed membrane traffic and fine-tuned cytoskeletal dynamics. In this study, we show that both processes are integrated in a positive feedback loop, mediated by the guanine nucleotide-exchange factor (GEF) Tuba. Tuba connects the activities of the Rab GTPase Rab8a and the Rho GTPase Cdc42, ensuring the generation of a single axon in cultured hippocampal neurons and controlling the migration of cortical neurons in the developing brain. Finally, we provide compelling evidence that Tuba is the GEF that mediates Cdc42 activation during the development of neuronal polarity.

  • axon specification
  • cytoskeleton
  • neuronal differentiation
  • neuronal polarity
  • Rab GTPases
  • Rho GTPases

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The Journal of Neuroscience: 41 (8)
Journal of Neuroscience
Vol. 41, Issue 8
24 Feb 2021
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Tuba Activates Cdc42 during Neuronal Polarization Downstream of the Small GTPase Rab8a
Pamela J. Urrutia, Felipe Bodaleo, Daniel A. Bórquez, Yuta Homma, Victoria Rozes-Salvador, Cristopher Villablanca, Cecilia Conde, Mitsunori Fukuda, Christian González-Billault
Journal of Neuroscience 24 February 2021, 41 (8) 1636-1649; DOI: 10.1523/JNEUROSCI.0633-20.2020

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Tuba Activates Cdc42 during Neuronal Polarization Downstream of the Small GTPase Rab8a
Pamela J. Urrutia, Felipe Bodaleo, Daniel A. Bórquez, Yuta Homma, Victoria Rozes-Salvador, Cristopher Villablanca, Cecilia Conde, Mitsunori Fukuda, Christian González-Billault
Journal of Neuroscience 24 February 2021, 41 (8) 1636-1649; DOI: 10.1523/JNEUROSCI.0633-20.2020
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Keywords

  • axon specification
  • cytoskeleton
  • neuronal differentiation
  • neuronal polarity
  • Rab GTPases
  • Rho GTPases

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