The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development.
Mutations in SALL4, the human homolog of the Drosophila homeotic gene spalt (sal), cause the autosomal dominant disorder known as Okihiro syndrome. In this study, we show that a targeted null mutation in the mouse Sall4 gene leads to lethality during peri-implantation. Growth of the inner cell mass from the knockout blastocysts was reduced, and Sall4-null embryonic stem (ES) cells proliferated poorly with no aberrant differentiation. Furthermore, we demonstrated that anorectal and heart anomalies in Okihiro syndrome are caused by Sall4 haploinsufficiency and that Sall4/Sall1 heterozygotes exhibited an increased incidence of anorectal and heart anomalies, exencephaly and kidney agenesis. Sall4 and Sall1 formed heterodimers, and a truncated Sall1 caused mislocalization of Sall4 in the heterochromatin; thus, some symptoms of Townes-Brocks syndrome caused by SALL1 truncations could result from SALL4 inhibition.
Sakaki-Yumoto
Masayo
M
Division of Integrative Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
Kobayashi
Chiyoko
C
Sato
Akira
A
Fujimura
Sayoko
S
Matsumoto
Yuko
Y
Takasato
Minoru
M
Kodama
Tatsuhiko
T
Aburatani
Hiroyuki
H
Asashima
Makoto
M
Yoshida
Nobuaki
N
Nishinakamura
Ryuichi
R
D000818:Animals; D001755:Blastocyst / Q000166:cytology; D001921:Brain / Q000196:embryology; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics*; D004370:Duane Retraction Syndrome / Q000235:genetics*; D006580:Genetic Carrier Screening; D005838:Genotype; D006321:Heart / Q000196:embryology; D007668:Kidney / Q000196:embryology; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics; D012007:Rectum / Q000196:embryology; D013234:Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection
D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; C491254:Sall1 protein, mouse; C509167:Sall4 protein, mouse; D014157:Transcription Factors