title: Neurog1 can partially substitute for Atoh1 function in hair cell differentiation and maintenance during organ of Corti development.
abstract: Atoh1, a basic helix-loop-helix (bHLH) transcription factor (TF), is essential for the differentiation of hair cells (HCs), mechanotransducers that convert sound into auditory signals in the mammalian organ of Corti (OC). Previous work demonstrated that replacing mouse Atoh1 with the fly ortholog atonal rescues HC differentiation, indicating functional replacement by other bHLH genes. However, replacing Atoh1 with Neurog1 resulted in reduced HC differentiation compared with transient Atoh1 expression in a 'self-terminating' Atoh1 conditional null mouse (Atoh1-Cre; Atoh1(f/f)). We now show that combining Neurog1 in one allele with removal of floxed Atoh1 in a self-terminating conditional mutant (Atoh1-Cre; Atoh1(f/kiNeurog1)) mouse results in significantly more differentiated inner HCs and outer HCs that have a prolonged longevity of 9 months compared with Atoh1 self-terminating littermates. Stereocilia bundles are partially disorganized, disoriented and not HC type specific. Replacement of Atoh1 with Neurog1 maintains limited expression of Pou4f3 and Barhl1 and rescues HCs quantitatively, but not qualitatively. OC patterning and supporting cell differentiation are also partially disrupted. Diffusible factors involved in patterning are reduced (Fgf8) and factors involved in cell-cell interactions are affected (Jag1, Hes5). Despite the presence of many HCs with stereocilia these mice are deaf, possibly owing to HC and OC patterning defects. This study provides a novel approach to disrupt OC development through modulating the HC-specific intracellular TF network. The resulting disorganized OC indicates that normally differentiated HCs act as 'self-organizers' for OC development and that Atoh1 plays a crucial role to initiate HC stereocilia differentiation independently of HC viability.
authors.affiliation: Department of Biology, College of Liberal Arts & Sciences, University of Iowa, Iowa City, IA 52242, USA israt-jahan@uiowa.edu bernd-fritzsch@uiowa.edu.
authors.forename: Israt
authors.initials: I
authors.lastname: Jahan
authors.affiliation: Department of Biology, College of Liberal Arts & Sciences, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Pan
authors.affiliation: Department of Biology, College of Liberal Arts & Sciences, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kersigo
authors.affiliation: Department of Biology, College of Liberal Arts & Sciences, University of Iowa, Iowa City, IA 52242, USA israt-jahan@uiowa.edu bernd-fritzsch@uiowa.edu.
authors.forename: Bernd
authors.initials: B
authors.lastname: Fritzsch
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D055879:Gene Knock-In Techniques; D006198:Hair Cells, Auditory / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008855:Microscopy, Electron, Scanning; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009925:Organ of Corti / Q000196:embryology*; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C500943:Atoh1 protein, mouse; C486336:Neurog1 protein, mouse
keywords: Basic helix-loop-helix; Hair cells; Knock-in; Misexpression; Survival; Transcription factors