In vivo notch reactivation in differentiating cochlear hair cells induces sox2 and prox1 expression but does not disrupt hair cell maturation
Year: 2012
Type: article
Abstract: BACKGROUND: Notch signaling is active in mouse cochlear prosensory progenitors but declines in differentiating sensory hair cells (HCs). Overactivation of the Notch1 intracellular domain (NICD) in progenitors blocks HC fate commitment and/or differentiation. However, it is not known whether reactivation of NICD in differentiating HCs also interrupts their developmental program and reactivates its downstream targets. RESULTS: By analyzing Atoh1(CreER+) ; Rosa26-NICD(loxp/+) or Atoh1(CreER+) ; Rosa26-NICD(loxp/+) ; RBP-J(loxp/loxp) mice, we demonstrated that ectopic NICD in differentiating HCs caused reactivation of Sox2 and Prox1 in an RBP-J-dependent manner. Interestingly, Prox1 reactivation was exclusive to outer HCs (OHCs). In addition, lineage tracing analysis of Prox1(CreER/+) ; Rosa26-EYFP(loxp/+) and Prox1(CreEGFP/+) ; Rosa26-EYFP(loxp/+) mice showed that nearly all HCs experiencing Prox1 expression were OHCs. Surprisingly, these HCs still matured normally with expression of prestin, wild-type-like morphology, and uptake of FM4-64FX dye at adult ages. CONCLUSIONS: Our results suggest that the developmental program of cochlear differentiating HCs is refractory to Notch reactivation and that Notch is an upstream regulator of Sox2 and Prox1 in cochlear development. In addition, our results support that Sox2 and Prox1 should not be the main blockers for terminal differentiation of HCs newly regenerated from postnatal cochlear SCs that still maintain Sox2 and Prox1 expression.
Source: Developmental Dynamics
DOI: 10.1002/dvdy.23754
Authors: Zhiyong Liu, Thomas Owen, Jie Fang, R. Sathish Srinivasan, Jian Zuo
Language: English
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
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: W2047170651