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Published on: February 21, 2016
Hearing loss associated with CDC42 in mice and humans (Takenouchi-Kosaki syndrome): CDC42 and RHOQ synergistically
Takehiko Ueyama1, Akira Ganaha2, Shunkou Kurasawa1
1Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe, Japan.
Abstract:
CDC42 is involved in multiple signaling pathways, including actin organization and polarity. We previously reported progressive sensorineural hearing loss (SNHL) in inner ear hair cell (HC)-specific Cdc42-knockout (Atoh1-Cre+/-;Cdc42flox/flox) mice. However, the phenotype was milder than expected, suggesting possible redundancy with other Rho-family GTPases. Thereafter, Takenouchi-Kosaki syndrome (TKS), caused by de novo CDC42 mutations and manifesting as SNHL, was reported, in which the p.Y64C mutation was speculated to be constitutively active. However, the relationship between CDC42 status and hearing phenotypes in TKS remains unclear. Using cell models, mouse models, and patient data, we propose that impaired and/or dysregulated cycling between GDP/inactive and GTP/active forms, through either loss-of-function or constitutive activation, can lead to SNHL. Furthermore, to test redundancy, we generated HC-specific Cdc42;RhoQ double-knockout (Atoh1-Cre+/-;Cdc42flox/flox;RhoQflox/flox) mice, which revealed synergistic roles of CDC42 and RHOQ in cochlear HCs. Supporting this synergy, MDCK cells with CDC42 and RHOQ double knockdown showed greater phospho-cofilin, a key regulator of actin turnover, elevation than single knockdowns.
Insights
Dysregulated CDC42 protein activity, whether reduced or overly active, causes sensorineural hearing loss (SNHL). This study reveals CDC42 and RHOQ act together in inner ear hair cells, impacting hearing.
Area of Science:
- Cell Biology
- Genetics
- Otolaryngology
Background:
- CDC42 is crucial for cell signaling, actin organization, and polarity.
- Sensorineural hearing loss (SNHL) has been observed in mice with inner ear hair cell-specific Cdc42 knockout.
- Takenouchi-Kosaki syndrome (TKS), linked to CDC42 mutations, also presents with SNHL.
Purpose of the Study:
- To investigate the role of CDC42 dysregulation in SNHL.
- To explore potential redundancy between CDC42 and other Rho-family GTPases in hearing.
- To clarify the relationship between CDC42 mutations and hearing phenotypes in TKS.
Main Methods:
- Utilized cell models, mouse models (including HC-specific Cdc42 and Cdc42;RhoQ double knockouts), and patient data.
- Analyzed the impact of altered CDC42 cycling (loss-of-function and constitutive activation) on SNHL.
- Assessed synergistic effects of CDC42 and RHOQ by examining phospho-cofilin levels in knockdown cells.
Main Results:
- Impaired or dysregulated CDC42 cycling (both loss-of-function and constitutive activation) leads to SNHL.
- HC-specific Cdc42;RhoQ double-knockout mice exhibit synergistic roles for CDC42 and RHOQ in cochlear hair cells.
- Double knockdown of CDC42 and RHOQ in MDCK cells resulted in a greater increase in phospho-cofilin than single knockdowns, indicating synergistic actin regulation.
Conclusions:
- Both loss-of-function and constitutive activation of CDC42 can cause SNHL.
- CDC42 and RHOQ play synergistic roles in maintaining cochlear hair cell function.
- Understanding CDC42's complex regulation is key to addressing SNHL and related genetic disorders like TKS.
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