TY - JOUR
T1 - Tuba activates cdc42 during neuronal polarization downstream of the small gtpase rab8a
AU - Urrutia, Pamela J.
AU - Bodaleo, Felipe
AU - Bórquez, Daniel A.
AU - Homma, Yuta
AU - Rozes-Salvador, Victoria
AU - Villablanca, Cristopher
AU - Conde, Cecilia
AU - Fukuda, Mitsunori
AU - González-Billault, Christian
N1 - Funding Information:
This work was supported by Comisión Nacional de Investigación Científica y Tecnológica grants to C.G.-B. under the Fondo Nacional de Ciencia y Tecnología (Fondecyt) (#1180419) and Fondo Nacional de Áreas Prioritarias (FONDAP) (#15150012) programs. P.U. was supported by the Fondecyt (#3160630) Postdoctoral program. C.G.-B. and C.C. were supported by the International Brain Research Organization (IBRO) PROLAB grant. We thank Dr. Michael Handford for language support and Cristina Olmos and Kazuyasu Shoji for technical assistance. The authors declare no competing financial interests. Correspondence should be addressed to Christian González-Billault at chrgonza@uchile.cl. https://doi.org/10.1523/JNEUROSCI.0633-20.2020 Copyright © 2021 the authors
Publisher Copyright:
© 2021 Society for Neuroscience. All rights reserved.
PY - 2021/2/24
Y1 - 2021/2/24
N2 - 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.
AB - 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.
KW - Axon specification
KW - Cytoskeleton
KW - Neuronal differentiation
KW - Neuronal polarity
KW - Rab gtpases
KW - Rho gtpases
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U2 - 10.1523/JNEUROSCI.0633-20.2020
DO - 10.1523/JNEUROSCI.0633-20.2020
M3 - Article
C2 - 33478991
AN - SCOPUS:85102322283
VL - 41
SP - 1636
EP - 1649
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 8
ER -