title: Correct timing of proliferation and differentiation is necessary for normal inner ear development and auditory hair cell viability.
abstract: BACKGROUND
  Hearing restoration through hair cell regeneration will require revealing the dynamic interactions between proliferation and differentiation during development to avoid the limited viability of regenerated hair cells. Pax2-Cre N-Myc conditional knockout (CKO) mice highlighted the need of N-Myc for proper neurosensory development and possible redundancy with L-Myc. The late-onset hair cell death in the absence of early N-Myc expression could be due to mis-regulation of genes necessary for neurosensory formation and maintenance, such as Neurod1, Atoh1, Pou4f3, and Barhl1.
  
  
  RESULTS
  Pax2-Cre N-Myc L-Myc double CKO mice show that proliferation and differentiation are linked together through Myc and in the absence of both Mycs, altered proliferation and differentiation result in morphologically abnormal ears. In particular, the organ of Corti apex is re-patterned into a vestibular-like organization and the base is truncated and fused with the saccule.
  
  
  CONCLUSIONS
  These data indicate that therapeutic approaches to restore hair cells must take into account a dynamic interaction of proliferation and differentiation regulation of basic Helix-Loop-Helix transcription factors in attempts to stably replace lost cochlear hair cells. In addition, our data indicate that Myc is an integral component of the evolutionary transformation process that resulted in the organ of Corti development.
authors.affiliation: University of Iowa, Department of Biology, Iowa City, IA 52242, USA. benjamin-kopecky@uiowa.edu
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Kopecky
authors.forename: Israt
authors.initials: I
authors.lastname: Jahan
authors.forename: Bernd
authors.initials: B
authors.lastname: Fritzsch
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D007758:Ear, Inner / Q000196:embryology*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005684:Gait / Q000502:physiology; D005838:Genotype; D006198:Hair Cells, Auditory / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D019426:Integrases; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal / Q000379:methods; D051762:PAX2 Transcription Factor / Q000378:metabolism; D010671:Phenylurea Compounds; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012038:Regeneration / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
chemical_list: C489428:Myc protein, mouse; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D010671:Phenylurea Compounds; D016271:Proto-Oncogene Proteins c-myc; C032766:ethylene diurea; C045073:Cre recombinase; D019426:Integrases