Project Number: 1F31DC018198-01
Contact PI / Project Leader: GILELS, FELICIA AILEEN
Title: THE ROLE OF NOTCH SIGNALING IN THE MAINTENANCE AND FUNCTION OF COCHLEAR SENSORY CELLS
Awardee Organization: UNIVERSITY OF ROCHESTER
The six sensory organs of the mammalian inner ear function to mediate hearing and balance. Mechanosensory hair cells, supporting cells, and spiral ganglion neurons are three essential cell types that comprise the inner ear sensory regions. Hearing loss is commonly caused by damage to these essential cell types which, in mammals, lack the capacity to regenerate. Thus, identifying signaling pathways that are involved in the development and maintenance of these cell types is of great importance. Notch has been shown to play two essential roles in embryonic inner ear sensory development: 1) establishes the prosensory progenitors that give rise to hair cells and supporting cells, and 2) mediates which cell fate is adopted by the sensory precursor, either hair cell or supporting cell. Despite these important early roles, there is a limited understanding of the function of Notch signaling postnatally. The Notch ligand Jagged1 (JAG1) has dynamic expression throughout inner ear development, and is the only reported Notch ligand maintained into adulthood where it is expressed in supporting cells. Here, to understand the role of JAG1-Notch signaling in the postnatal inner ear we utilize a Cre/loxP recombination system to conditionally delete either JAG1 or Notch receptors in supporting cells at postnatal day (P)0/P1 and assess for effects on hearing and cochlear morphology. Preliminary results indicate that JAG1 signaling is required postnatally for normal hearing function, as Sox2-Jag1cko mice display a specific form of hearing loss termed auditory neuropathy, that specifically affects the inner hair cell pathway. In Aim 1, we will determine how JAG1 signaling functions in maturation and/or maintenance of the postnatal cochlea and test our hypothesis that postnatal JAG1 signaling influences stereocilia morphogenesis and/or maintenance. In Aim 2, we will identify the Notch receptor mediating the effects of JAG1 in the postnatal cochlea and test the hypothesis that JAG1 signals through the Notch1 and/or Notch2 receptor(s) in postnatal cochlear supporting cells. Our preliminary data suggests Notch1 may be the predominant JAG1 receptor as Sox2-Notch1cko mice show profound deafness at 6-weeks of age. These studies will elucidate novel functions for JAG1-Notch signaling in hearing maturation and/or maintenance in the postnatal cochlea.
Public Health Relevance Statement:
Hearing and vestibular disorders commonly occur from loss or damage to critical cell types (mechanosensitive hair cells, supporting cells, and spiral ganglion neurons), which in mature mammals are not replaced. Potential therapeutic strategies to treat these disorders may involve cell replacement or regenerative therapies; however, a prerequisite for this approach is the identification of signaling pathways involved in the development and maintenance of these cell types. Elucidating novel functions for JAG1-Notch signaling, previously implicated in establishing embryonic prosensory progenitors and mediating progenitor cell fate adaptation, will create insights into the molecular mechanisms of hearing maturation/maintenance in the postnatal cochlea; this knowledge will provide a platform for future therapies designed to restore inner ear function.