Charcot-Marie-Tooth 2b associated Rab7 mutations cause axon growth and guidance defects during vertebrate sensory neuron development

Neural Development
Olga Y PonomarevaMary C Halloran

Abstract

Charcot-Marie-Tooth2b (CMT2b) is an axonal form of a human neurodegenerative disease that preferentially affects sensory neurons. CMT2b is dominantly inherited and is characterized by unusually early onset, presenting in the second or third decade of life. Five missense mutations in the gene encoding Rab7 GTPase have been identified as causative in human CMT2b disease. Although several studies have modeled CMT2b disease in cultured neurons and in Drosophila, the mechanisms by which defective Rab7 leads to disease remain poorly understood. We used zebrafish to investigate the effects of CMT2b-associated Rab7 mutations in a vertebrate model. We generated transgenic animals expressing the CMT2b-associated mutant forms of Rab7 in sensory neurons, and show that these Rab7 variants cause neurodevelopmental defects, including defects in sensory axon growth, branching and pathfinding at early developmental stages. We also find reduced axon growth and branching in neurons expressing a constitutively active form of Rab7, suggesting these defects may be caused by Rab7 gain-of-function. Further, we use high-speed, high-resolution imaging of endosome transport in vivo and find that CMT2b-associated Rab7 variants cause reduced vesicle speeds...Continue Reading

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Citations

Feb 7, 2017·International Journal of Molecular Sciences·Harry Liu, Chengbiao Wu
Dec 15, 2017·Small GTPases·Marcellus J Banworth, Guangpu Li
May 27, 2016·Molecular Biology of the Cell·Nicholas R DavenportWilliam M Bement
Sep 4, 2018·FEBS Letters·David Villarroel-CamposOscar Marcelo Lazo
Aug 21, 2019·Cells·Noemi Antonella Guadagno, Cinzia Progida
Oct 18, 2019·The Journal of Cell Biology·Guang WangHui-Yan Li
Mar 7, 2019·Frontiers in Cell and Developmental Biology·Valérie BercierCéline Revenu
Apr 14, 2020·Cellular and Molecular Life Sciences : CMLS·Roberta RomanoCecilia Bucci
Jun 17, 2018·The Journal of Cell Biology·Chan Choo YapBettina Winckler
Mar 28, 2017·F1000Research·James N SleighGiampietro Schiavo
Sep 29, 2019·Journal of Neuromuscular Diseases·Danique BeijerVincent Timmerman
Mar 7, 2021·International Journal of Molecular Sciences·Veselina PetrovaRichard Eva
Aug 24, 2020·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Anna Maria GiudettiCecilia Bucci
Mar 8, 2020·Journal of Molecular Biology·Frédéric Darios, Giovanni Stevanin
Nov 3, 2017·Neuron·Marco TerenzioMike Fainzilber

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Methods Mentioned

BETA
GTPase
transgenic
transgenics

Software Mentioned

ImageJ
GraphPad
Prism
Volocity

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