Notch signaling in cell-fate specification and maintenance in the developing and adult mammalian inner ear.

摘要

The inner ear contains the auditory and vestibular organs, which are sensory neuroepithelia composed of mechanosensory hair cells and glia-like supporting cells. The mammalian auditory sensory epithelium, the organ of Corti, is responsible for transduction of sound stimuli into electrical signals for hearing function. Hair cells are susceptible to damage from noise, toxins, and ageing. Mammals do not regenerate hair cells after damage, but non-mammalian vertebrates are capable of hair cell regeneration. Replacement of lost hair cells in lower vertebrates occurs through plasticity of supporting cells, which directly change fate into hair cells or proliferate to produce new cells through a recapitulation of developmental mechanisms. However, supporting cells in the mature mammalian cochlea do not exhibit the potential to change fate or proliferate in order to regenerate lost sensory cells. However, during embryonic development, hair cells and supporting cells develop from common precursors and the fate of individual cells is regulated through intercellular signaling and genetic mechanisms. The overall goal of this research is to further understand the mechanisms of specification and maintenance of sensory cell fates in the developing and adult mammalian inner ear.Understanding the way in which cell types are developed and maintained is a crucial step in overcoming the barriers to regeneration in the mammalian inner ear. A key regulator of development in the inner ear is the Notch signaling pathway, a highly conserved cell signaling system present in most multicellular organisms. In this dissertation, after a review of relevant literature, I will describe our investigation of Notch signaling in the developing and adult mammalian inner ear. We conducted comprehensive gene expression analyses and describe novel expression patterns of two Notch ligands, DII3 and DNER, and a key Notch effector, Hes5. We found that the Notch pathway is highly active during cochlear development but appears to be absent from the adult cochlea. We performed several transgenic gain-of-function experiments, which show that Notch signal activation during development is capable of conferring prosensory character to regions of nonsensory epithelia. However, constitutive activation of Notch in mature cochlear supporting cells was not sufficient to confer regeneration potential.