Individual USH2 proteins make distinct contributions to the ankle link complex during development of the mouse cochlear stereociliary bundle
- PMID: 26401052
- PMCID: PMC4654051
- DOI: 10.1093/hmg/ddv398
Individual USH2 proteins make distinct contributions to the ankle link complex during development of the mouse cochlear stereociliary bundle
Abstract
Usher syndrome (USH) is the leading cause of inherited deaf-blindness, with type 2 (USH2) being the most common clinical form. Studies suggest that proteins encoded by USH2 causative genes assemble into the ankle link complex (ALC) at the hair cell stereociliary bundle; however, little is known about the in vivo assembly and function of this complex. Using various USH2 mutant mice, we showed by immunofluorescence that USH2 proteins play different roles in cochlear ALC assembly, with G protein-coupled receptor 98 being the most important protein. Complex assembly likely occurs at the stereociliary bundle but not along the protein transport route in the cell body. Stereociliary morphological defects in USH2 mutant mice suggest roles for the ALC in regulating inner hair cell stereociliary growth and differentiation as well as outer hair cell stereociliary rigidity and organization during development. These roles are unique from the bundle cohesion role of Usher syndrome type 1 protein complexes. Loss of individual USH2 gene expressions leads to variable morphological and functional consequences, correlating with the severity of ALC disruption. This finding suggests a potential genotype-phenotype correlation in USH2 patients. In summary, this study provides novel insights into the molecular mechanism underlying cochlear stereociliary bundle development and hearing loss pathogenesis of various USH2 subtypes. Our thorough phenotypical characterization of USH2 mouse models is essential for future use of these animal models in therapeutic development.
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Figures
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4654051/bin/ddv39801.gif)
![Figure 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4654051/bin/ddv39802.gif)
![Figure 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4654051/bin/ddv39803.gif)
![Figure 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4654051/bin/ddv39804.gif)
![Figure 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4654051/bin/ddv39805.gif)
![Figure 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4654051/bin/ddv39806.gif)
![Figure 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4654051/bin/ddv39807.gif)
![Figure 8.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4654051/bin/ddv39808.gif)
![Figure 9.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4654051/bin/ddv39809.gif)
![Figure 10.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4654051/bin/ddv39810.gif)
![Figure 11.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4654051/bin/ddv39811.gif)
Similar articles
-
The roles of USH1 proteins and PDZ domain-containing USH proteins in USH2 complex integrity in cochlear hair cells.Hum Mol Genet. 2017 Feb 1;26(3):624-636. doi: 10.1093/hmg/ddw421. Hum Mol Genet. 2017. PMID: 28031293 Free PMC article.
-
Deletion of PDZD7 disrupts the Usher syndrome type 2 protein complex in cochlear hair cells and causes hearing loss in mice.Hum Mol Genet. 2014 May 1;23(9):2374-90. doi: 10.1093/hmg/ddt629. Epub 2013 Dec 11. Hum Mol Genet. 2014. PMID: 24334608 Free PMC article.
-
Whirlin and PDZ domain-containing 7 (PDZD7) proteins are both required to form the quaternary protein complex associated with Usher syndrome type 2.J Biol Chem. 2014 Dec 26;289(52):36070-88. doi: 10.1074/jbc.M114.610535. Epub 2014 Nov 18. J Biol Chem. 2014. PMID: 25406310 Free PMC article.
-
Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease.Exp Eye Res. 2006 Jul;83(1):97-119. doi: 10.1016/j.exer.2005.11.010. Epub 2006 Mar 20. Exp Eye Res. 2006. PMID: 16545802 Review.
-
Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina.Hear Res. 2019 Apr;375:14-24. doi: 10.1016/j.heares.2019.02.007. Epub 2019 Feb 22. Hear Res. 2019. PMID: 30831381 Free PMC article. Review.
Cited by
-
A Consolidated Understanding of the Contribution of Redox Dysregulation in the Development of Hearing Impairment.Antioxidants (Basel). 2024 May 13;13(5):598. doi: 10.3390/antiox13050598. Antioxidants (Basel). 2024. PMID: 38790703 Free PMC article. Review.
-
Expression of the human usherin c.2299delG mutation leads to early-onset auditory loss and stereocilia disorganization.Commun Biol. 2023 Sep 12;6(1):933. doi: 10.1038/s42003-023-05296-x. Commun Biol. 2023. PMID: 37700068 Free PMC article.
-
Successful large gene augmentation of USH2A with non-viral episomal vectors.Mol Ther. 2023 Sep 6;31(9):2755-2766. doi: 10.1016/j.ymthe.2023.06.012. Epub 2023 Jun 19. Mol Ther. 2023. PMID: 37337429
-
A protein domain-oriented approach to expand the opportunities of therapeutic exon skipping for USH2A-associated retinitis pigmentosa.Mol Ther Nucleic Acids. 2023 May 20;32:980-994. doi: 10.1016/j.omtn.2023.05.020. eCollection 2023 Jun 13. Mol Ther Nucleic Acids. 2023. PMID: 37313440 Free PMC article.
-
Adenylyl cyclase 6 plays a minor role in the mouse inner ear and retina.Sci Rep. 2023 May 1;13(1):7075. doi: 10.1038/s41598-023-34361-y. Sci Rep. 2023. PMID: 37127773 Free PMC article.
References
-
- Assad J.A., Shepherd G.M., Corey D.P. (1991) Tip-link integrity and mechanical transduction in vertebrate hair cells. Neuron, 7, 985–994. - PubMed
-
- Hudspeth A.J. (1985) Models for mechanoelectrical transduction by hair cells. Prog. Clin. Biol. Res., 176, 193–205. - PubMed
-
- Frolenkov G.I., Belyantseva I.A., Friedman T.B., Griffith A.J. (2004) Genetic insights into the morphogenesis of inner ear hair cells. Nat. Rev. Genet., 5, 489–498. - PubMed
-
- Nayak G.D., Ratnayaka H.S., Goodyear R.J., Richardson G.P. (2007) Development of the hair bundle and mechanotransduction. Int. J. Dev. Biol., 51, 597–608. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases