Overactivation of Notch1 Signaling Induces Ectopic Hair Cells in the Mouse Inner Ear in an Age-Dependent Manner
Year: 2012
Type: article
Abstract: BACKGROUND: During 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 FINDINGS: We performed comprehensive in vivo inducible overactivation of NICD at various developmental stages. In CAG(CreER+); Rosa26-NICD(loxp/+) 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/SIGNIFICANCE: Our 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.
Source: PLoS ONE
Authors: Zhiyong Liu, Thomas Owen, Jie Fang, Jian Zuo
Language: English
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: National Organization for Hearing Research Foundation, St. Jude Children's Research Hospital, American Lebanese Syrian Associated Charities, National Institutes of Health, Health Science Center, University of Tennessee, Office of Naval Research, National Cancer Institute, National Institute on Deafness and Other Communication Disorders
Awards: G164415112, Genetic analysis of mammalian hearing sensitivity, G1955015674, Generation of mice with inducible Cre expression in adult cochlear hair cells, G4177576686, G4856111422, CONDITIONAL GENE TARGETING IN HAIR CELLS, G609259107, G6298368088, G751896108, G865138149, G9000086855, Cancer Center Support Grant (CCSG)
OpenAlex ID: W2057365749