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Severe ciliopathy-related phenotypes in mice with dysregulation of tubulin polyglutamylation

Tubulin, a main component of ciliary and flagellar axonemes, undergoes highly unique post-translational modifications, polyglutamylation and polyglycylation. Recent years, evidence accumulates that dysregulations of these two modifications lead to severe ciliary defects in a variety of model organisms, such as Chlamydomonas, Tetrahymena, C. elegans, Drosophila, and zebrafish. Previously, we have for the first time revealed that a reduction of tubulin polyglutamylation causes ciliopathy-related defects including severe respiratory problems, such as paranasal sinusitis and repetitive coughing or sneezing, and male infertility by means of a knockout mouse of a glutamate ligase (TTLL1KO) [Ikegami et al. 2010 PNAS]. Despite the clear ciliopathy-related defects by the loss of polyglutamylation-performing enzyme, it is still veiled whether over-polyglutamylation leads to ciliopathy-related phenotypes in mice. To address the question, we examined the retina of a spontaneous mutant of a glutamate-removing enzyme (pcd) mouse that displays late-onset retinal photoreceptor degeneration. The pcd mouse showed stronger polyglutamylation signals in the retinal cone and rod layer compared to wild-type animal. To test if the hyper-polyglutamylation leads to retinal degeneration, we generated a double mutant of pcd and TTLL1KO. The hyper-polyglutamylation observed in the cone and rod layer of pcd mice was neutralized in that of pcd/TTLL1KO double mutant. The retinal photoreceptor degeneration in pcd was almost completely rescued in the pcd/TTLL1KO double mutant. These results suggest that hyper-polyglutamylation underlies retinal photoreceptor degeneration. We would emphasize, in the conference, the importance of keeping narrow range of polyglutamylation level to maintain ciliary function.

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Correspondence to K Ikegami.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Ikegami, K., Konno, A., Hattori, S. et al. Severe ciliopathy-related phenotypes in mice with dysregulation of tubulin polyglutamylation. Cilia 1 (Suppl 1), P90 (2012).

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