title: Prox1 interacts with Atoh1 and Gfi1, and regulates cellular differentiation in the inner ear sensory epithelia.
abstract: Inner ear hair cells and supporting cells arise from common precursors and, in mammals, do not show phenotypic conversion. Here, we studied the role of the homeodomain transcription factor Prox1 in the inner ear sensory epithelia. Adenoviral-mediated Prox1 transduction into hair cells in explant cultures led to strong repression of Atoh1 and Gfi1, two transcription factors critical for hair cell differentiation and survival. Luciferase assays showed that Prox1 can repress transcriptional activity of Gfi1 independently of Atoh1. Prox1 transduction into cochlear outer hair cells resulted in degeneration of these cells, consistent with the known phenotype of Gfi1-deficient mice. These results together with the widespread expression of endogenous Prox1 within the population of inner ear supporting cells point to the role for Prox1 in antagonizing the hair cell phenotype in these non-sensory cells. Further, in vivo analyses of hair cells from Gfi1-deficient mice suggest that the cyclin-dependent kinase inhibitor p57(Kip2) mediates the differentiation- and survival-promoting functions of Gfi1. These data reveal novel gene interactions and show that these interactions regulate cellular differentiation within the inner ear sensory epithelia. The data point to the tight regulation of phenotypic characteristics of hair cells and supporting cells.
authors.affiliation: Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kirjavainen
authors.forename: Marilin
authors.initials: M
authors.lastname: Sulg
authors.forename: Florian
authors.initials: F
authors.lastname: Heyd
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
authors.forename: Ulla
authors.initials: U
authors.lastname: Pirvola
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D003051:Cochlea / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D007758:Ear, Inner / Q000166:cytology / Q000196:embryology*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D006198:Hair Cells, Auditory / Q000166:cytology / Q000378:metabolism / Q000821:virology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D009924:Organ Culture Techniques; D012444:Saccule and Utricle / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; C500943:Atoh1 protein, mouse; C493965:Cdkn1c protein, mouse; C079873:Gfi1 protein, mouse