title: Molecular mechanisms underlying inner ear patterning defects in kreisler mutants.
abstract: Prior studies have shown that kreisler mutants display early inner ear defects that are related to abnormal hindbrain development and signaling. These defects in kreisler mice have been linked to mutation of the kr/mafB gene. To investigate potential relevance of kr/mafB and abnormal hindbrain development in inner ear patterning, we analyzed the ear morphogenesis in kreisler mice using a paint-fill technique. We also examined the expression patterns of a battery of genes important for normal inner ear patterning and development. Our results indicate that the loss of dorsal otic structures such as the endolymphatic duct and sac is attributable to the downregulation of Gbx2, Dlx5 and Wnt2b in the dorsal region of the otocyst. In contrast, the expanded expression domain of Otx2 in the ventral otic region likely contributes to the cochlear phenotype seen in kreisler mutants. Sensory organ development is also markedly disrupted in kreisler mutants. This pattern of defects and gene expression changes is remarkably similar to that observed in Gbx2 mutants. Taken together, the data show an important role for hindbrain cues, and indirectly, kr/mafB, in guiding inner ear morphogenesis. The data also identify Gbx2, Dlx5, Wnt2b and Otx2 as key otic genes ultimately affected by perturbation of the kr/mafB-hindbrain pathway.
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Center for Hearing and Deafness Research, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, OH 45229-3039, USA. daniel.choo@cchmc.org
authors.forename: Daniel
authors.initials: D
authors.lastname: Choo
authors.forename: Jaye
authors.initials: J
authors.lastname: Ward
authors.forename: Alisa
authors.initials: A
authors.lastname: Reece
authors.forename: Hongwei
authors.initials: H
authors.lastname: Dou
authors.forename: Zhengshi
authors.initials: Z
authors.lastname: Lin
authors.forename: John
authors.initials: J
authors.lastname: Greinwald
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019521:Body Patterning / Q000235:genetics* / Q000502:physiology; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D003051:Cochlea / Q000196:embryology / Q000378:metabolism; D007758:Ear, Inner / Q000196:embryology* / Q000378:metabolism*; D004711:Endolymphatic Duct / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D017403:In Situ Hybridization; D051258:MafB Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009024:Morphogenesis / Q000235:genetics; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051857:Otx Transcription Factors / Q000378:metabolism; D012249:Rhombencephalon / Q000196:embryology / Q000378:metabolism; D012665:Semicircular Canals / Q000196:embryology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; C501120:Dlx5 protein, mouse; C513182:Gbx2 protein, mouse; D006023:Glycoproteins; D018398:Homeodomain Proteins; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D015513:Oncogene Proteins; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D051153:Wnt Proteins; C492031:Wnt2b protein, mouse