The role of Six1 in mammalian auditory system development.
The homeobox Six genes, homologues to Drosophila sine oculis (so) gene, are expressed in multiple organs during mammalian development. However, their roles during auditory system development have not been studied. We report that Six1 is required for mouse auditory system development. During inner ear development, Six1 expression was first detected in the ventral region of the otic pit and later is restricted to the middle and ventral otic vesicle within which, respectively, the vestibular and auditory epithelia form. By contrast, Six1 expression is excluded from the dorsal otic vesicle within which the semicircular canals form. Six1 is also expressed in the vestibuloacoustic ganglion. At E15.5, Six1 is expressed in all sensory epithelia of the inner ear. Using recently generated Six1 mutant mice, we found that all Six1(+/-) mice showed some degree of hearing loss because of a failure of sound transmission in the middle ear. By contrast, Six1(-/-) mice displayed malformations of the auditory system involving the outer, middle and inner ears. The inner ear development in Six1(-/-) embryos arrested at the otic vesicle stage and all components of the inner ear failed to form due to increased cell death and reduced cell proliferation in the otic epithelium. Because we previously reported that Six1 expression in the otic vesicle is Eya1 dependent, we first clarified that Eya1 expression was unaffected in Six1(-/-) otic vesicle, further demonstrating that the Drosophila Eya-Six regulatory cassette is evolutionarily conserved during mammalian inner ear development. We also analyzed several other otic markers and found that the expression of Pax2 and Pax8 was unaffected in Six1(-/-) otic vesicle. By contrast, Six1 is required for the activation of Fgf3 expression and the maintenance of Fgf10 and Bmp4 expression in the otic vesicle. Furthermore, loss of Six1 function alters the expression pattern of Nkx5.1 and Gata3, indicating that Six1 is required for regional specification of the otic vesicle. Finally, our data suggest that the interaction between Eya1 and Six1 is crucial for the morphogenesis of the cochlea and the posterior ampulla during inner ear development. These analyses establish a role for Six1 in early growth and patterning of the otic vesicle.
Zheng
Weiming
W
McLaughlin Research Institute for Biomedical Sciences, 1520 23rd Street South, Great Falls, MT 59405, USA.
Huang
Li
L
Wei
Zhu-Bo
ZB
Silvius
Derek
D
Tang
Bihui
B
Xu
Pin-Xian
PX
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D007758:Ear, Inner / Q000196:embryology*; D051526:Fibroblast Growth Factor 10; D051518:Fibroblast Growth Factor 3; D005346:Fibroblast Growth Factors / Q000378:metabolism; D050990:GATA3 Transcription Factor; D034381:Hearing Loss / Q000196:embryology / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins; D051762:PAX2 Transcription Factor; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C496464:Fgf10 protein, mouse; C489197:Fgf3 protein, mouse; D051526:Fibroblast Growth Factor 10; D051518:Fibroblast Growth Factor 3; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C086187:Hmx3 protein, mouse; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051762:PAX2 Transcription Factor; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C497319:Pax2 protein, mouse; C499496:Pax8 protein, mouse; D011518:Proto-Oncogene Proteins; C490947:Six1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D005346:Fibroblast Growth Factors; C501156:Eya1 protein, mouse; D017027:Protein Tyrosine Phosphatases