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
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
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DOI：
10.1242/dev.02457
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发表时间：
2006-08-01
期刊：
影响因子：
4.6
通讯作者：
Nishinakamura, Ryuichi
中科院分区：
文献类型：
--
作者：
Sakaki-Yumoto, Masayo;Kobayashi, Chiyoko;Nishinakamura, Ryuichi
SALL4（果蝇同源异型基因 spalt (sal) 的人类同源物）的突变会导致常染色体显性遗传疾病，称为 Okihiro 综合征。在这项研究中，我们发现小鼠 Sall4 基因中的靶向无效突变会导致植入期间的死亡。敲除囊胚的内细胞团生长减少，Sall4 缺失的胚胎干 (ES) 细胞增殖不良，没有异常分化。此外，我们证明 Okihiro 综合征中的肛门直肠和心脏异常是由 Sall4 单倍体不足引起的，并且 Sall4/Sall1 杂合子表现出肛门直肠和心脏异常、脑外畸形和肾脏发育不全的发生率增加。 Sall4和Sall1形成异二聚体，截短的Sall1导致Sall4在异染色质中的错误定位；因此，由 SALL1 截短引起的 Townes-Brocks 综合征的一些症状可能是由 SALL4 抑制引起的。
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.