title: An RNA interference-based screen of transcription factor genes identifies pathways necessary for sensory regeneration in the avian inner ear.
abstract: Sensory hair cells of the inner ear are the mechanoelectric transducers of sound and head motion. In mammals, damage to sensory hair cells leads to hearing or balance deficits. Nonmammalian vertebrates such as birds can regenerate hair cells after injury. In a previous study, we characterized transcription factor gene expression during chicken hair cell regeneration. In those studies, a laser microbeam or ototoxic antibiotics were used to damage the sensory epithelia (SE). The current study focused on 27 genes that were upregulated in regenerating SEs compared to untreated SEs in the previous study. Those genes were knocked down by siRNA to determine their requirement for supporting cell proliferation and to measure resulting changes in the larger network of gene expression. We identified 11 genes necessary for proliferation and also identified novel interactive relationships between many of them. Defined components of the WNT, PAX, and AP1 pathways were shown to be required for supporting cell proliferation. These pathways intersect on WNT4, which is also necessary for proliferation. Among the required genes, the CCAAT enhancer binding protein, CEBPG, acts downstream of Jun Kinase and JUND in the AP1 pathway. The WNT coreceptor LRP5 acts downstream of CEBPG, as does the transcription factor BTAF1. Both of these genes are also necessary for supporting cell proliferation. This is the first large-scale screen of its type and suggests an important intersection between the AP1 pathway, the PAX pathway, and WNT signaling in the regulation of supporting cell proliferation during inner ear hair cell regeneration.
authors: Division of Human Genetics, Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors: David M
authors: DM
authors: Alvarado
authors: R David
authors: RD
authors: Hawkins
authors: Stavros
authors: S
authors: Bashiardes
authors: Rose A
authors: RA
authors: Veile
authors: Yuan-Chieh
authors: YC
authors: Ku
authors: Kara E
authors: KE
authors: Powder
authors: Meghan K
authors: MK
authors: Spriggs
authors: Judith D
authors: JD
authors: Speck
authors: Mark E
authors: ME
authors: Warchol
authors: Michael
authors: M
authors: Lovett
mesh_terms: D000818:Animals; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002645:Chickens; D007758:Ear, Inner / Q000502:physiology*; D004848:Epithelium / Q000502:physiology; D055785:Gene Knockdown Techniques; D006199:Hair Cells, Auditory, Inner / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D007834:Lasers; D046228:Microarray Analysis; D009416:Nerve Regeneration / Q000502:physiology*; D051419:Paxillin / Q000235:genetics / Q000502:physiology; D034622:RNA Interference / Q000502:physiology*; D012444:Saccule and Utricle / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000502:physiology; D035362:Transcription Factor TFIID / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*; D051153:Wnt Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D060528:Wnt4 Protein
chemical_list: D023081:CCAAT-Binding Factor; D051419:Paxillin; D018808:Transcription Factor AP-1; D035362:Transcription Factor TFIID; D014157:Transcription Factors; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; D048031:JNK Mitogen-Activated Protein Kinases