cAMP-induced Auditory Supporting Cell Proliferation is Mediated by ERK MAPK Signaling Pathway

Abstract

Sensorineural hearing deficiencies result from the loss of auditory hair cells. This hearing loss is permanent in humans and mammals because hair cells are not spontaneously replaced. In other animals such as birds, this is not the case. Damage to the avian cochlea evokes proliferation of supporting cells and the generation of functionally competent replacement hair cells. Signal transduction pathways are clinically useful as potential therapeutic targets, so there is significant interest in identifying the key signal transduction pathways that regulate the formation of replacement hair cells. In a previous study from our lab, we showed that forskolin (FSK) treatment induces auditory supporting cell proliferation and formation of replacement hair cells in the absence of sound or aminoglycoside treatment. Here, we show that FSK-induced supporting cell proliferation is mediated by cell-specific accumulation of cyclic adenosine monophosphate (cAMP) in avian supporting cells and the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. By a combination of immunostaining and pharmacological analyses, we show that FSK treatment increases cAMP levels in avian auditory supporting cells and that several ERK MAP inhibitors effectively block FSK-induced supporting cell proliferation. Next, we demonstrate by Western blotting and immunostaining analyses the expression of several ERK MAPK signaling molecules in the avian auditory epithelium and the cell-specific expression of B-Raf in avian auditory supporting cells. Collectively, these data suggest that FSK-induced supporting cell proliferation in the avian auditory epithelium is mediated by increases of cAMP levels in supporting cells and the cell-specific expression of the ERK MAPK family member B-Raf in supporting cells.

Transcription factor STOX1 regulates proliferation of inner ear epithelial cells via the AKT pathway

“…We found that after STOX1 knockdown in cultured epithelial cells, expression of markers for proliferation (PCNA and cyclin A, cyclin E) (26,42) was significantly reduced, but up-regulated following STOX1 over-expression. During mammalian organogenesis, the AKT pathway regulates both cell proliferation and programmed cell death (11,43). Our results further show that shSTOX1 inhibited phosphorylation of AKT in the inner ear utricular epithelial cells, while over-expression of STOX1 activated phosphorylation of AKT.…”

Inhibitory effect of SLIT2 on granulosa cell proliferation mediated by the CDC42-PAKs-ERK1/2 MAPK pathway in the prehierarchical follicles of the chicken ovary

“…Furthermore, the Raf kinases play an important and specific role in the activation of the MAPK/ERK cascade 36 . For example, B-RAF can be activated by the cAMP/PKA pathway, which leads to increases in the levels of ERK-1/2 activity in supporting cells expressing B-Raf in the avian auditory epithelium 37 . The elevated expression levels of cAMP and B-Raf have been reported to increase the levels of cell proliferation in cultured neuronal cells 38 .…”

Insulin-like growth factor 1 inhibits hair cell apoptosis and promotes the cell cycle of supporting cells by activating different downstream cascades after pharmacological hair cell injury in neonatal mice

“…Inner sulcus cells might provide some surviving factors to adjacent IHCs. In contrast, the MEK/ERK pathway was likely to be involved in the cell cycle promotion of the Hensen's and Claudius' cells for two reasons: p-ERK was detected in the Hensen's and Claudius' cells ( Figure 3F) in which BrdU uptake and pHH3 were also detected, and the activation of MEK/ERK pathway causes the proliferation of SCs in the chicken basilar papillae, resulting in the regeneration of HCs (Bell and Oberholtzer, 2010).…”