Abstract
BackgroundCharcot-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.ResultsWe 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, suggesting altered transport may underlie axon development defects.ConclusionsOur data provide new insight into how disease-associated alterations in Rab7 protein disrupt cellular function in vertebrate sensory neurons. Moreover, our findings suggest that defects in axon development may be a previously unrecognized component of CMT2b disease.
Highlights
Charcot-Marie-Tooth2b (CMT2b) is an axonal form of a human neurodegenerative disease that preferentially affects sensory neurons
Peripheral sensory neuron outgrowth and branching are reduced in CMT2b Rab7 mutant expressing neurons To investigate the effects of CMT2b mutations in a vertebrate model, we used zebrafish Rohon-Beard (RB) spinal sensory neurons
We quantified axon branching by counting the number of peripheral axon endings and found a significant reduction in the number of branches in neurons expressing any of the four CMT2b Rab7 mutants (Fig. 1g)
Summary
Charcot-Marie-Tooth2b (CMT2b) is an axonal form of a human neurodegenerative disease that preferentially affects sensory neurons. CMT2b is an autosomal dominant disease, caused by five missense mutations in Ponomareva et al Neural Development (2016) 11:2 domains, and affect GDP and GTP exchange, increasing both Rab activation and hydrolysis-dependent inactivation, resulting in a form of Rab that is prone to remain in the active, GTP-bound form [12,13,14]. This finding, together with the dominant inheritance of the human disease, has led to the hypothesis that the disease is caused by overactivity of Rab. The mutations do not interfere with the ability of Rab to bind its effector RILP and in some cases CMT2b Rab mutants are able to rescue Rab loss of function [12, 13, 15], which suggests retention of some wildtype function
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