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Sonic Hedgehog repression underlies gigaxonin mutation–induced motor deficits in giant axonal neuropathy
Yoan Arribat, … , Mireille Rossel, Pascale Bomont
Yoan Arribat, … , Mireille Rossel, Pascale Bomont
Published September 10, 2019
Citation Information: J Clin Invest. 2019;129(12):5312-5326. https://doi.org/10.1172/JCI129788.
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Research Article Neuroscience

Sonic Hedgehog repression underlies gigaxonin mutation–induced motor deficits in giant axonal neuropathy

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Abstract

Growing evidence shows that alterations occurring at early developmental stages contribute to symptoms manifested in adulthood in the setting of neurodegenerative diseases. Here, we studied the molecular mechanisms causing giant axonal neuropathy (GAN), a severe neurodegenerative disease due to loss-of-function of the gigaxonin–E3 ligase. We showed that gigaxonin governs Sonic Hedgehog (Shh) induction, the developmental pathway patterning the dorso-ventral axis of the neural tube and muscles, by controlling the degradation of the Shh-bound Patched receptor. Similar to Shh inhibition, repression of gigaxonin in zebrafish impaired motor neuron specification and somitogenesis and abolished neuromuscular junction formation and locomotion. Shh signaling was impaired in gigaxonin-null zebrafish and was corrected by both pharmacological activation of the Shh pathway and human gigaxonin, pointing to an evolutionary-conserved mechanism regulating Shh signaling. Gigaxonin-dependent inhibition of Shh activation was also demonstrated in primary fibroblasts from patients with GAN and in a Shh activity reporter line depleted in gigaxonin. Our findings establish gigaxonin as a key E3 ligase that positively controls the initiation of Shh transduction, and reveal the causal role of Shh dysfunction in motor deficits, thus highlighting the developmental origin of GAN.

Authors

Yoan Arribat, Karolina S. Mysiak, Léa Lescouzères, Alexia Boizot, Maxime Ruiz, Mireille Rossel, Pascale Bomont

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Figure 3

The gandel/del zebrafish, similar to gan morphants, exhibit Shh-like deficits.

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The gandel/del zebrafish, similar to gan morphants, exhibit Shh-like def...
(A) Schematic representation of the deletion within the endogenous gan locus, and genotyping of the gandel/del line. (B–D) gandel/del embryos display locomotor deficits. (B) Quantification of the touch-evoked response of gandel/del embryos at 72 hpf; n = 82 (WT), n = 110 (gandel/del). (C) Tracking analysis of the spontaneous locomotion of 5 dpf control and mutant larvae. (D) Quantification of total distance traveled (top) and net velocity (bottom) at 5 dpf in the control (n = 24) and gandel/del (n = 64) populations. Statistics: in the absence of normality of distribution of the data, a 2-tailed Mann Whitney U test was applied; medians with interquartile range, minimum, and maximum values are represented; *P < 0.05. (E) Nkx6.1 and Islet immunostaining at 36 hpf is significantly decreased in the gan line in 84% of mutants (n = 21 of 25 analyzed embryos). (F) Zn8 immunostaining reveals a strong defect in sMN axonal projections at 56 hpf in 72% of gandel/del mutants (n = 18 of 25 analyzed embryos). Scale bars: 25 μm (E); 100 μm (F).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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