Six1 controls patterning of the mouse otic vesicle.
Six1 is a member of the Six family homeobox genes, which function as components of the Pax-Six-Eya-Dach gene network to control organ development. Six1 is expressed in otic vesicles, nasal epithelia, branchial arches/pouches, nephrogenic cords, somites and a limited set of ganglia. In this study, we established Six1-deficient mice and found that development of the inner ear, nose, thymus, kidney and skeletal muscle was severely affected. Six1-deficient embryos were devoid of inner ear structures, including cochlea and vestibule, while their endolymphatic sac was enlarged. The inner ear anomaly began at around E10.5 and Six1 was expressed in the ventral region of the otic vesicle in the wild-type embryos at this stage. In the otic vesicle of Six1-deficient embryos, expressions of Otx1, Otx2, Lfng and Fgf3, which were expressed ventrally in the wild-type otic vesicles, were abolished, while the expression domains of Dlx5, Hmx3, Dach1 and Dach2, which were expressed dorsally in the wild-type otic vesicles, expanded ventrally. Our results indicate that Six1 functions as a key regulator of otic vesicle patterning at early embryogenesis and controls the expression domains of downstream otic genes responsible for respective inner ear structures. In addition, cell proliferation was reduced and apoptotic cell death was enhanced in the ventral region of the otic vesicle, suggesting the involvement of Six1 in cell proliferation and survival. In spite of the similarity of otic phenotypes of Six1- and Shh-deficient mice, expressions of Six1 and Shh were mutually independent.
Ozaki
Hidenori
H
Division of Biology, Center for Molecular Medicine, Jichi Medical School, Tochigi 329-0498, Japan.
Nakamura
Kazuaki
K
Funahashi
Jun-ichi
J
Ikeda
Keiko
K
Yamada
Gen
G
Tokano
Hisashi
H
Okamura
Hiro-oki
HO
Kitamura
Ken
K
Muto
Shigeaki
S
Kotaki
Hayato
H
Sudo
Katsuko
K
Horai
Reiko
R
Iwakura
Yoichiro
Y
Kawakami
Kiyoshi
K
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D019521:Body Patterning / Q000502:physiology*; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D007758:Ear, Inner / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D004432:Ear, Middle / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000196:embryology; D051379:Mice; D018482:Muscle, Skeletal / Q000196:embryology; D009666:Nose / Q000196:embryology; D015398:Signal Transduction / Q000502:physiology; D013950:Thymus Gland / Q000196:embryology; D015534:Trans-Activators / Q000502:physiology
D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C490947:Six1 protein, mouse; D015534:Trans-Activators