Abstract
BackgroundDuring mouse inner ear development, Notch1 signaling first specifies sensory progenitors, and subsequently controls progenitors to further differentiate into either hair cells (HCs) or supporting cells (SCs). Overactivation of NICD (Notch1 intracellular domain) at early embryonic stages leads to ectopic HC formation. However, it remains unclear whether such an effect can be elicited at later embryonic or postnatal stages, which has important implications in mouse HC regeneration by reactivation of Notch1 signaling.Methodology/Principal FindingsWe performed comprehensive in vivo inducible overactivation of NICD at various developmental stages. In CAGCreER+; Rosa26-NICDloxp/+ mice, tamoxifen treatment at embryonic day 10.5 (E10.5) generated ectopic HCs in the non-sensory regions in both utricle and cochlea, whereas ectopic HCs only appeared in the utricle when tamoxifen was given at E13. When tamoxifen was injected at postnatal day 0 (P0) and P1, no ectopic HCs were observed in either utricle or cochlea. Interestingly, Notch1 signaling induced new HCs in a non-cell-autonomous manner, because the new HCs did not express NICD. Adjacent to the new HCs were cells expressing the SC marker Sox10 (either NICD+ or NICD-negative).Conclusions/SignificanceOur data demonstrate that the developmental stage determines responsiveness of embryonic otic precursors and neonatal non-sensory epithelial cells to NICD overactivation, and that Notch 1 signaling in the wild type, postnatal inner ear is not sufficient for generating new HCs. Thus, our genetic mouse model is suitable to test additional pathways that could synergistically interact with Notch1 pathway to produce HCs at postnatal ages.
Highlights
The mouse inner ear is a well-organized sensory organ responsible for balance and hearing [1,2,3,4]
We demonstrated that overactivation of NICD at embryonic ages but not neonatal ages resulted in the formation of ectopic sensory epithelia in non-sensory regions and supernumerary hair cells (HCs) in sensory regions
As NICD and EGFP transcriptions are coupled by the same Rosa26 promoter, EGFP will faithfully reflect NICD expression and serve as a lineage
Summary
The mouse inner ear is a well-organized sensory organ responsible for balance and hearing [1,2,3,4] It emanates from a thickening ectoderm adjacent to the hindbrain at approximately embryonic day 8 (E8), referred to as the otic placode, which continues to invaginate and morph into the otocyst [5,6] at approximately E10. During mouse inner ear development, Notch signaling first specifies sensory progenitors, and subsequently controls progenitors to further differentiate into either hair cells (HCs) or supporting cells (SCs). Overactivation of NICD (Notch intracellular domain) at early embryonic stages leads to ectopic HC formation It remains unclear whether such an effect can be elicited at later embryonic or postnatal stages, which has important implications in mouse HC regeneration by reactivation of Notch signaling
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