Abstract
c-Myb is a transcription factor that plays a key role in cell proliferation, differentiation, and apoptosis. It has been reported that c-Myb is expressed within the chicken otic placode, but whether c-Myb exists in the mammalian cochlea, and how it exerts its effects, has not been explored yet. Here, we investigated the expression of c-Myb in the postnatal mouse cochlea and HEI-OC1 cells and found that c-Myb was expressed in the hair cells (HCs) of mouse cochlea as well as in cultured HEI-OC1 cells. Next, we demonstrated that c-Myb expression was decreased in response to neomycin treatment in both cochlear HCs and HEI-OC1 cells, suggesting an otoprotective role for c-Myb. We then knocked down c-Myb expression with shRNA transfection in HEI-OC1 cells and found that c-Myb knockdown decreased cell viability, increased expression of pro-apoptotic factors, and enhanced cell apoptosis after neomycin insult. Mechanistic studies revealed that c-Myb knockdown increased cellular levels of reactive oxygen species and decreased Bcl-2 expression, both of which are likely to be responsible for the increased sensitivity of c-Myb knockdown cells to neomycin. This study provides evidence that c-Myb might serve as a new target for the prevention of aminoglycoside-induced HC loss.
Highlights
Hearing loss is one of the most common sensory disorders in humans, and it affects the life quality of the afflicted individuals, and imposes a heavy social and economic burden on families and the community
It has been reported that c-Myb is present within the chicken otic placode – a specialized region that gives rise to the components of the inner ear – and that c-Myb plays a role in controlling the onset of Sox[10] expression, which serves as a key marker for otic development[27]
Immunostaining showed that there was no expression of c-Myb in the P1 cochlea, and the expression of c-Myb was almost undetectable at P7 (Fig. 1). c-Myb expression was present at a low level in outer hair cells (HCs) (OHCs) from P11, but not in inner HCs (IHCs) or supporting cell (SC) (Fig. 1)
Summary
Hearing loss is one of the most common sensory disorders in humans, and it affects the life quality of the afflicted individuals, and imposes a heavy social and economic burden on families and the community. It is well known that these HCs are susceptible to death from aminoglycosides, non-steroidal anti-inflammatory drugs, noise, and aging. Excess ROS overwhelms the redox balance and skews cell metabolism toward the activation of intrinsic apoptosis, which is regulated by the combined actions of pro- and anti-apoptotic members of the Bcl-2 family[7,8,9]. The overexpression of c-Myb promotes cell cycle progression and prevents apoptosis[21]. The mechanism behind this activity involves positive regulation of the anti-apoptotic gene Bcl-213,22–24 and negative regulation of ROS generation in cardiomyocytes[25]. The present study was designed to determine the expression pattern of c-Myb in the mammalian inner ear and to investigate the function of c-Myb in HEI-OC1 cells
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