Abstract
Embryonic development requires the coordinated regulation of apoptosis, survival, autophagy, proliferation and differentiation programs. Senescence has recently joined the cellular processes required to master development, in addition to its well-described roles in cancer and ageing. Here, we show that senescent cells are present in a highly regulated temporal pattern in the developing vertebrate inner ear, first, surrounding the otic pore and, later, in the otocyst at the endolymphatic duct. Cellular senescence is associated with areas of increased apoptosis and reduced proliferation consistent with the induction of the process when the endolymphatic duct is being formed. Modulation of senescence disrupts otic vesicle morphology. Transforming growth factor beta (TGFβ) signaling interacts with signaling pathways elicited by insulin-like growth factor type 1 (IGF-1) to jointly coordinate cellular dynamics required for morphogenesis and differentiation. Taken together, these results show that senescence is a natural occurring process essential for early inner ear development.
Highlights
The vertebrate inner ear is the organ that senses sound, movement and position
HH17 embryos showed marked staining of SAβG in the otic epithelium, with the highest levels observed around the otic pore (Fig. 1A), an area of known intense apoptosis[30]
Dissected otic vesicles from mouse E10 and HH19 chicken embryos showed that senescence is highly restricted to the developing endolymphatic duct in both species (Fig. 1D,E), suggesting that otic senescence is dynamic and developmentally-regulated
Summary
Most of the cell types that populate the adult vestibular and auditory parts of the inner ear have a common developmental origin in the otic placode[1]. These cell types include sensory hair cells, supporting cells, secretory cells and neurons for the vestibular and acoustic ganglia, all spatially organized with a fine-tuned geometry matched for the functions of hearing and equilibrium[2]. Developmental senescence acts together with apoptosis in the elimination of unwanted cells as well as in patterning and morphogenesis[14] It shares most of the cellular characteristics of oncogene-induced senescence, such as arrested proliferation, increased SAβG staining and a secretory phenotype. Senescent cells secrete TGFβ, IGFBPs and cytokines among other pro-inflammatory, anti-proliferative and pro-apoptotic signals[15]
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