title: Hedgehog signaling regulates sensory cell formation and auditory function in mice and humans.
abstract: Auditory perception is mediated through a finite number of mechanosensory hair cells located in a specialized sensory epithelium within the inner ear. The formation of the appropriate number of hair cells and the location of those cells is crucial for normal auditory function. However, the factors that regulate the formation of this epithelium remain poorly understood. Truncating mutations in the transcription factor GLI3, a downstream effector of the Hedgehog (HH) pathway, lead to a partial loss of HH signaling and cause Pallister-Hall syndrome (PHS). Here, we report that cochleae from a mouse model of PHS (Gli3(Delta699)), which produces only the truncated, repressor form of GLI3, have a variably penetrant phenotype that includes an increase in the size of the sensory epithelium and the development of large ectopic sensory patches in Kölliker's organ (KO). Consistent with the mouse model, some PHS individuals exhibit hearing loss across a broad range of frequencies. Moreover, inhibition of HH signaling in vitro results in an increase in the size of the prosensory domain, a precursor population that gives rise to the sensory epithelium, whereas treatment with Sonic hedgehog (SHH) inhibits prosensory formation. Finally, we demonstrate that HH signaling within the cochlea regulates expression of prosensory markers and that the effects of HH in KO are dependent on activation of Notch, an inducer of prosensory fate. These results suggest that HH signaling plays a key role in the specification, size, and location of the prosensory domain, and therefore of hair cells, within the cochlea.
authors.affiliation: Section on Developmental Neuroscience, National Institute on Deafness and Other Communication Disorders, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. drivere@nidcd.nih.gov
authors.forename: Elizabeth Carroll
authors.initials: EC
authors.lastname: Driver
authors.forename: Shannon P
authors.initials: SP
authors.lastname: Pryor
authors.forename: Patrick
authors.initials: P
authors.lastname: Hill
authors.forename: Joyce
authors.initials: J
authors.lastname: Turner
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rüther
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Griffith
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kelley
mesh_terms: D000818:Animals; D001307:Auditory Perception / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D003051:Cochlea / Q000196:embryology / Q000473:pathology / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006198:Hair Cells, Auditory / Q000473:pathology / Q000502:physiology; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D009475:Neurons, Afferent / Q000473:pathology / Q000502:physiology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D000074290:Zinc Finger Protein Gli3
chemical_list: C065683:GLI3 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3