Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in inner ears of Foxi1 null mutant mice.
Mice that lack the winged helix/forkhead gene Foxi1 (also known as Fkh10) are deaf and display shaker/waltzer behavior, an indication of disturbed balance. While Foxi1 is expressed in the entire otic vesicle at E9.5, it becomes gradually restricted to the endolymphatic duct/sac epithelium and at E16.5 Foxi1 expression in the inner ear is confined to this epithelium. Histological sections, paintfill experiments and whole-mount hybridizations reveal no abnormality in inner ear development of Foxi1(-/-) mice before E13.5. Between E13.5 and E16.5 the membranous labyrinth of inner ears from null mutants starts to expand as can be seen in histological sections, paint-fill experiments and three-dimensional reconstruction. Postnatally, inner ears of Foxi1(-/-) mice are extremely expanded, and large irregular cavities, compressing the cerebellum and the otherwise normal middle ear, have replaced the delicate compartments of the wild-type inner ear. This phenotype resembles that of the human sensorineural deafness syndrome Pendred syndrome, caused by mutations in the PDS gene. In situ hybridization of Foxi1(-/-) endolymphatic duct/sac epithelium shows a complete lack of the transcript encoding the chloride/iodide transporter pendrin. Based on this, we would like to suggest that Foxi1 is an upstream regulator of pendrin and that the phenotype seen in Foxi1 null mice is, at least in part, due to defective pendrin-mediated chloride ion resorption in the endolymphatic duct/sac epithelium. We show that this regulation could be mediated by absence of a specific endolymphatic cell type--FORE (forkhead related) cells--expressing Foxi1, Pds, Coch and Jag1. Thus, mutations in FOXI1 could prove to cause a Pendred syndrome-like human deafness.
Hulander
Malin
M
Medical Genetics, Department of Medical Biochemistry, Institute of Anatomy and Cell Biology, Göteborg University, Box 440, SE-405 30 Göteborg, Sweden.
Kiernan
Amy E
AE
Blomqvist
Sandra Rodrigo
SR
Carlsson
Peter
P
Samuelsson
Emma-Johanna
EJ
Johansson
Bengt R
BR
Steel
Karen P
KP
Enerbäck
Sven
S
D000818:Animals; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003638:Deafness / Q000235:genetics* / Q000378:metabolism; D004848:Epithelium / Q000002:abnormalities / Q000196:embryology; D051858:Forkhead Transcription Factors; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D000076988:Sulfate Transporters; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014723:Vestibular Aqueduct / Q000002:abnormalities / Q000196:embryology*
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009687:Nuclear Proteins; D011506:Proteins; C085609:SLC26A4 protein, human; D000072099:Serrate-Jagged Proteins; D000076988:Sulfate Transporters; D014157:Transcription Factors