Giese, Arnaud PJ;
Parker, Andrew;
Rehman, Sakina;
Brown, Steve DM;
Riazuddin, Saima;
Kooi, Craig W Vander;
Bowl, Michael R;
(2025)
CIB2 function is distinct from Whirlin in the development of cochlear stereocilia staircase pattern.
Disease Models & Mechanisms
10.1242/dmm.052043.
(In press).
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Abstract
Humans and mice with mutations in genes encoding CIB2 and whirlin (WHRN) are deaf. We previously reported that CIB2 binds to WHRN and is essential for stereocilia staircase architecture of cochlear hair cells. Here, we refine the interaction domains of both proteins and show that these proteins play unique roles in stereocilia bundle formation and organization. We found that the EF2 domain of CIB2 binds to the HHD2 region of WHRN. AlphaFold2 multimer independently identified same interacting regions and gave a thorough structural model. Next, we investigated genetic interaction between murine Cib2 and Whrn. Hearing in mice double heterozygous for functionally null alleles (Cib2KO/+;Whrnwi/+) was similar to age-matched wild-type mice, indicating that partial deficiency for both Cib2 and Whrn does not impair hearing. Double homozygous mutant mice (Cib2KO/KO;Whrnwi/wi) were deaf, and their cochlear stereocilia exhibited a predominant phenotype seen in single Whrnwi/wi mutants. Over-expression of WHRN in Cib2KO/KO mice did not rescue the stereocilia morphology. These data suggest that CIB2 is multifunctional, with key independent functions in the development and/or maintenance of the stereocilia staircase pattern in auditory hair cells.
| Type: | Article |
|---|---|
| Title: | CIB2 function is distinct from Whirlin in the development of cochlear stereocilia staircase pattern |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1242/dmm.052043 |
| Publisher version: | https://doi.org/10.1242/dmm.052043 |
| Language: | English |
| Additional information: | Copyright © 2025. Published by The Company of Biologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
| Keywords: | CIB2, Whirlin, WHRN, Inner ear hair cells, Stereocilia staircase, Cochlea |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > The Ear Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10206891 |
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