Notch Inhibition Induces Cochlear Hair Cell Regeneration and Recovery of Hearing after Acoustic Trauma

Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02115, USA
Neuron (Impact Factor: 15.05). 01/2013; 77(1):58-69. DOI: 10.1016/j.neuron.2012.10.032
Source: PubMed


Hearing loss due to damage to auditory hair cells is normally irreversible because mammalian hair cells do not regenerate. Here, we show that new hair cells can be induced and can cause partial recovery of hearing in ears damaged by noise trauma, when Notch signaling is inhibited by a γ-secretase inhibitor selected for potency in stimulating hair cell differentiation from inner ear stem cells in vitro. Hair cell generation resulted from an increase in the level of bHLH transcription factor Atoh1 in response to inhibition of Notch signaling. In vivo prospective labeling of Sox2-expressing cells with a Cre-lox system unambiguously demonstrated that hair cell generation resulted from transdifferentiation of supporting cells. Manipulating cell fate of cochlear sensory cells in vivo by pharmacological inhibition of Notch signaling is thus a potential therapeutic approach to the treatment of deafness. VIDEO ABSTRACT:

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Available from: Makoto Hosoya, Aug 25, 2015
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    • "The compartmentalized expression of Notch and Wnt pathway members and their expression changes during regeneration suggest that they might be involved in controlling proliferation and differentiation in distinct regions of homeostatic and regenerating NMs. Inhibition of Notch Signaling Mimics Expression Changes Observed during Regeneration To test if the Notch and Wnt pathways regulate each other, we inhibited Notch signaling using the g-secretase inhibitor LY411575, referred to as ''LY'' (Mizutari et al., 2013). Because Notch signaling exhibits dose-dependent effects, we treated larvae with 10 and 50 mM of LY (Chapouton et al., 2010; Ninov et al., 2012). "
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    ABSTRACT: In vertebrates, mechano-electrical transduction of sound is accomplished by sensory hair cells. Whereas mammalian hair cells are not replaced when lost, in fish they constantly renew and regenerate after injury. In vivo tracking and cell fate analyses of all dividing cells during lateral line hair cell regeneration revealed that support and hair cell progenitors localize to distinct tissue compartments. Importantly, we find that the balance between self-renewal and differentiation in these compartments is controlled by spatially restricted Notch signaling and its inhibition of Wnt-induced proliferation. The ability to simultaneously study and manipulate individual cell behaviors and multiple pathways in vivo transforms the lateral line into a powerful paradigm to mechanistically dissect sensory organ regeneration. The striking similarities to other vertebrate stem cell compartments uniquely place zebrafish to help elucidate why mammals possess such low capacity to regenerate hair cells. Copyright © 2015 Elsevier Inc. All rights reserved.
    Developmental Cell 07/2015; 34(3). DOI:10.1016/j.devcel.2015.05.025 · 9.71 Impact Factor
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    • "l . 2005 ; Jahan et al . 2013 ; Matei et al . 2005 ) . When exactly such fate reversals are irreversible in the ear neurosensory precursors remains to be experimentally evalu - ated . If properly understood , it has the potential to reverse existing decisions and convert any cell type in the organ of Corti into hair cells , as recently suggested ( Mizutari et al . 2013 ) . It is important for this fate reversal to understand the molecular basis of such decision making to enhance the fre - quency of the outcome and the stability of the induced transdifferentiation . In this context , level of expression of differentiation - inducing bHLH genes , as mediated by early transcription factors in the otic pl"
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    ABSTRACT: Understanding the evolution of the neurosensory system of man, able to reflect on its own origin, is one of the major goals of comparative neurobiology. Details of the origin of neurosensory cells, their aggregation into central nervous systems and associated sensory organs and their localized patterning leading to remarkably different cell types aggregated into variably sized parts of the central nervous system have begun to emerge. Insights at the cellular and molecular level have begun to shed some light on the evolution of neurosensory cells, partially covered in this review. Molecular evidence suggests that high mobility group (HMG) proteins of pre-metazoans evolved into the definitive Sox [SRY (sex determining region Y)-box] genes used for neurosensory precursor specification in metazoans. Likewise, pre-metazoan basic helix-loop-helix (bHLH) genes evolved in metazoans into the group A bHLH genes dedicated to neurosensory differentiation in bilaterians. Available evidence suggests that the Sox and bHLH genes evolved a cross-regulatory network able to synchronize expansion of precursor populations and their subsequent differentiation into novel parts of the brain or sensory organs. Molecular evidence suggests metazoans evolved patterning gene networks early, which were not dedicated to neuronal development. Only later in evolution were these patterning gene networks tied into the increasing complexity of diffusible factors, many of which were already present in pre-metazoans, to drive local patterning events. It appears that the evolving molecular basis of neurosensory cell development may have led, in interaction with differentially expressed patterning genes, to local network modifications guiding unique specializations of neurosensory cells into sensory organs and various areas of the central nervous system.
    Cell and Tissue Research 11/2014; 359(1). DOI:10.1007/s00441-014-2043-1 · 3.57 Impact Factor
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    • "An additional caveat of Notch inhibition is that defects in hair cell polarity are observed in developing and regenerating zebrafish (Mirkovic et al., 2012; Wibowo et al., 2011). Hair cell polarity has not been characterized in the mouse or chicken after Notch downregulation (Mizutari et al., 2013; Daudet et al., 2009 "
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    ABSTRACT: Background: Damage or destruction of sensory hair cells in the inner ear leads to hearing or balance deficits that can be debilitating, especially in older adults. Unfortunately, the damage is permanent, as regeneration of the inner ear sensory epithelia does not occur in mammals. Results: Zebrafish and other non-mammalian vertebrates have the remarkable ability to regenerate sensory hair cells and understanding the molecular and cellular basis for this regenerative ability will hopefully aid us in designing therapies to induce regeneration in mammals. Zebrafish not only possess hair cells in the ear but also in the sensory lateral line system. Hair cells in both organs are functionally analogous to hair cells in the inner ear of mammals. The lateral line is a mechanosensory system found in most aquatic vertebrates that detects water motion and aids in predator avoidance, prey capture, schooling, and mating. Although hair cell regeneration occurs in both the ear and lateral line, most research to date has focused on the lateral line due to its relatively simple structure and accessibility. Conclusions: Here we review the recent discoveries made during the characterization of hair cell regeneration in zebrafish.
    Developmental Dynamics 10/2014; 243(10). DOI:10.1002/dvdy.24167 · 2.38 Impact Factor
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