title: Activated notch causes deafness by promoting a supporting cell phenotype in developing auditory hair cells.
abstract: OBJECTIVE
  To determine whether activated Notch can promote a supporting cell fate during sensory cell differentiation in the inner ear.
  
  
  METHODS
  An activated form of the Notch1 receptor (NICD) was expressed in early differentiating hair cells using a Gfi1-Cre mouse allele. To determine the effects of activated Notch on developing hair cells, Gfi1-NICD animals and their littermate controls were assessed at 5 weeks for hearing by measuring auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). The differentiation of NICD-expressing hair cells was assessed at postnatal day (P) 6, 11 and 20, using histological and molecular markers for hair cells, as well as supporting cells/progenitor cells. We also examined whether the effects of Notch were mediated by SOX2, a gene expressed in supporting cells and a likely downstream target of Notch, by crossing an inducible form of SOX2 to the Gfi1-Cre.
  
  
  RESULTS
  Activation of Notch1 in developing auditory hair cells causes profound deafness. The NICD-expressing hair cells switch off a number of hair cell markers and lose their characteristic morphology. Instead, NICD-expressing hair cells adopt a morphology resembling supporting cells and upregulate a number of supporting cell markers. These effects do not appear to be mediated by SOX2, because although expression of SOX2 caused some hearing impairment, the SOX2-expressing hair cells did not downregulate hair cell markers nor exhibit a supporting cell-like phenotype.
  
  
  CONCLUSIONS
  Our data show that Notch signaling inhibits hair cell differentiation and promotes a supporting cell-like phenotype, and that these effects are unlikely to be mediated by SOX2.
authors.affiliation: Department of Ophthalmology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Grace
authors.initials: G
authors.lastname: Savoy-Burke
authors.affiliation: Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Felicia A
authors.initials: FA
authors.lastname: Gilels
authors.affiliation: Department of Ophthalmology, University of Rochester Medical Center, Rochester, New York, United States of America; Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Ophthalmology, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Pratt
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Que
authors.affiliation: Department of Ophthalmology, University of Rochester Medical Center, Rochester, New York, United States of America; Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Gan
authors.affiliation: Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: White
authors.affiliation: Department of Ophthalmology, University of Rochester Medical Center, Rochester, New York, United States of America; Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Kiernan
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D003638:Deafness / Q000209:etiology*; D015536:Down-Regulation; D006199:Hair Cells, Auditory, Inner / Q000166:cytology* / Q000378:metabolism; D006320:Hearing Tests; D051379:Mice; D010641:Phenotype; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D051881:Receptor, Notch1; D051880:Receptors, Notch; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse