Bai C B, Joyner A L
Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Development. 2001 Dec;128(24):5161-72. doi: 10.1242/dev.128.24.5161.
In mice, three Gli genes are thought to mediate sonic hedgehog (Shh) signaling collectively. Mis-expression studies and analysis of null mutants for each gene have indicated that the Gli proteins have different functions. In particular, Gli1 appears to be a constitutive activator, and Gli2 and Gli3 have repressor functions. To determine the precise functional differences between Gli1 and Gli2, we have expressed Gli1 in place of Gli2 from the endogenous Gli2 locus in mice. Strikingly, a low level of Gli1 can rescue all the Shh signaling defects in Gli2 mutants; however, only in the presence of a wild-type Shh gene. These studies demonstrate that only the activator function of Gli2 is actually required, and indicates that in specific situations, Shh can modulate the ability of Gli1 to activate target genes. Furthermore, expression of both copies of Gli1 in place of Gli2 does not disrupt spinal cord patterning, but does result in new gain-of-function defects that lead to lethality. We show that the defects are enhanced when Gli3 function is reduced, demonstrating that an important difference between Gli1 and Gli2 is the ability of Gli1 to antagonize Gli3 function.
在小鼠中，三个Gli基因被认为共同介导音猬因子（Shh）信号传导。对每个基因的错误表达研究和无效突变体分析表明，Gli蛋白具有不同的功能。特别是，Gli1似乎是一种组成型激活剂，而Gli2和Gli3具有抑制功能。为了确定Gli1和Gli2之间的确切功能差异，我们已在小鼠的内源性Gli2基因座处表达Gli1以替代Gli2。令人惊讶的是，低水平的Gli1可以挽救Gli2突变体中的所有Shh信号缺陷；然而，仅在存在野生型Shh基因的情况下。这些研究表明，实际上只需要Gli2的激活功能，并表明在特定情况下，Shh可以调节Gli1激活靶基因的能力。此外，用Gli1替代Gli2的两个拷贝进行表达不会破坏脊髓模式，但确实会导致新的功能获得性缺陷，从而导致致死性。我们表明，当Gli3功能降低时，缺陷会增强，这表明Gli1和Gli2之间的一个重要差异是Gli1拮抗Gli3功能的能力。
