Abstract
Mechanosensory hair cells (HCs) and surrounding supporting cells (SCs) in the mouse cochlea are important for hearing and are derived from the same prosensory progenitors. Notch1 signaling plays dual but contrasting and age-dependent roles in mouse cochlear development: early lateral induction and subsequent lateral inhibition. However, it has been difficult to directly visualize mouse cochlear cells experiencing various levels of Notch1 activity at single cell resolution. Here, we characterized two knock-in mouse lines, Notch1Cre (Low)/+ and Notch1Cre (High)/+, with different Cre recombinase activities, that can detect Notch1 receptor proteolysis or Notch1 activity at high and low thresholds, respectively. Using both lines together with a highly sensitive Cre reporter line, we showed that Notch1 activity is nearly undetectable during lateral induction but increases to medium and high levels during lateral inhibition. Furthermore, we found that within the neonatal organ of Corti, the vast majority of cells that experience Notch1 activity were SCs not HCs, suggesting that HCs kept undetectable Notch1 activity during the entire lineage development. Furthermore, among SC subtypes, ∼85–99% of Deiters’ and outer pillar cells but only ∼19–38% of inner pillar cells experience medium and high levels of Notch1 activity. Our results demonstrate that Notch1 activity is highly heterogeneous: 1) between lateral induction and inhibition; 2) between HC and SC lineages; 3) among different SC subtypes; 4) among different cells within each SC subtype. Such heterogeneity should elucidate how the development of the cochclear sensory epithelium is precisely controlled and how HC regeneration can be best achieved in postnatal cochleae.
Highlights
Sound detection in the mammalian inner ear is mediated via mechanosensory hair cells (HCs) in the sensory epithelium of the cochlea, referred to as the organ of Corti [1,2,3,4]
The organ of Corti contains three rows of outer hair cells (OHCs) and one row of inner hair cells (IHCs), which are surrounded by different types of supporting cells (SCs): inner pillar cells (IPCs), outer pillar cells (OPCs) and Deiters’ cells (DCs) [1]
Extra Sox2+ SCs were found in the same confocal scanning area where ectopic OHCs were present at P6 (Fig. 1B’–D’; n = 3)
Summary
Sound detection in the mammalian inner ear is mediated via mechanosensory hair cells (HCs) in the sensory epithelium of the cochlea, referred to as the organ of Corti [1,2,3,4]. The period between E14 and perinatal ages is the lateral inhibition phase, when prosensory progenitors undergo differentiation and Notch signaling promotes SC’s, but antagonizes HC’s, fate commitment and differentiation [18,19]. It remains unknown how Notch signaling evokes such dual but contrasting effects in the development of the inner ear and how cochlear cells sense and respond appropriately to Notch signaling at different developmental stages.
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