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PMID: 12874121 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The role of Six1 in mammalian auditory system development.

Development (Cambridge, England) ·Vol. 130 ·No. 17 ·2003-09-00 ·Pages 3989-4000

Zheng W, Huang L, Wei ZB, Silvius D, Tang B, Xu PX

Abstract

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.

MeSH Terms
Animals Bone Morphogenetic Protein 4 Bone Morphogenetic Proteins/metabolism DNA-Binding Proteins/metabolism Ear, Inner/embryology Fibroblast Growth Factor 10 Fibroblast Growth Factor 3 Fibroblast Growth Factors/metabolism GATA3 Transcription Factor Hearing Loss/embryology,genetics Homeodomain Proteins/metabolism Intracellular Signaling Peptides and Proteins Mice Nerve Tissue Proteins/metabolism Nuclear Proteins PAX2 Transcription Factor PAX8 Transcription Factor Paired Box Transcription Factors Protein Tyrosine Phosphatases Proto-Oncogene Proteins/metabolism Trans-Activators/metabolism Transcription Factors/metabolism
Chemicals
Bmp4 protein, mouse Bone Morphogenetic Protein 4 Bone Morphogenetic Proteins DNA-Binding Proteins Fgf10 protein, mouse Fgf3 protein, mouse Fibroblast Growth Factor 10 Fibroblast Growth Factor 3 GATA3 Transcription Factor Gata3 protein, mouse Hmx3 protein, mouse Homeodomain Proteins Intracellular Signaling Peptides and Proteins Nerve Tissue Proteins Nuclear Proteins PAX2 Transcription Factor PAX8 Transcription Factor Paired Box Transcription Factors Pax2 protein, mouse Pax8 protein, mouse Proto-Oncogene Proteins Six1 protein, mouse Trans-Activators Transcription Factors Fibroblast Growth Factors Eya1 protein, mouse Protein Tyrosine Phosphatases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Zheng Weiming
McLaughlin Research Institute for Biomedical Sciences, 1520 23rd Street South, Great Falls, MT 59405, USA.
Huang Li
Wei Zhu-Bo
Silvius Derek
Tang Bihui
Xu Pin-Xian
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Article Info
Journal
Development (Cambridge, England)
Abbr.
Development
ISSN
0950-1991
DOI
10.1242/dev.00628
Published
2003-09-00
Pages
3989-4000
Language
English
Region
England
NLM ID
8701744
PMCID
PMC3873880
Subset
IM
Grants
NCRR NIH HHS · P20 RR015583 · United States
NIDCD NIH HHS · R01 DC005824 · United States
NCRR NIH HHS · P20 RR 15583 · United States
NIDCD NIH HHS · R01 DC 05824 · United States
External Links
PubMed source DOI: 10.1242/dev.00628 PMC Full Text View journal details
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