Yang J T, Liu C Z, Villavicencio E H, Yoon J W, Walterhouse D, Iannaccone P M
Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois, USA.
Mol Med. 1997 Dec;3(12):826-35.
GLI is an oncodevelopmental gene in the vertebrate hedgehog/patched signaling pathway that is spatiotemporally regulated during development and is amplified in a subset of human cancers. GLI is the prototype for the Gli-Kruppel family of transcription factors, which includes the Drosophila segment polarity gene ci, the C. elegans sex-determining gene tra-1, and human and mouse GLI3, all of which contain a conserved domain of five C2-H2 zinc fingers. GLI3 mutations have been implicated in the mouse mutant extra toes, as well as in human Greig cephalopolydactaly syndrome and the autosomal dominant form of Pallister-Hall syndrome. As such, GLI and the vertebrate hedgehog/patched signaling pathway appear to play important roles in both normal development and neoplasia.
Since it is not known whether aberrant GLI expression is similarly linked to developmental disorders, we developed gain-of-function transgenic mice which express human GLI ectopically.
Affected transgenic mice exhibit a phenotype of failure to thrive, early death, and Hirschsprung-like patches of gastrointestinal dilatation. The colons of affected mice have greatly attenuated smooth muscle layers and abnormal overlying epithelium. The density of myenteric plexuses is reduced in the colonic walls. The severity of the phenotype is related to the level of transgene expression.
The transgenic mouse model supports a role for GLI in gastrointestinal development. As part of the vertebrate hedgehog/patched signaling pathway, GLI is essential to mesoderm and CNS ectoderm development and transgenic GLI expression affects neuronal, muscular, and epithelial cell differentiation in the gut. Expression of human GLI in mice results in impairment of enteric neuronal development and a Hirschsprung-like phenotype.
GLI是脊椎动物刺猬信号通路/ patched信号通路中的一个肿瘤发生发展相关基因，在发育过程中受到时空调控，并且在一部分人类癌症中发生扩增。GLI是Gli-Kruppel转录因子家族的原型，该家族包括果蝇节段极性基因ci、秀丽隐杆线虫性别决定基因tra-1以及人类和小鼠的GLI3，它们都含有一个由五个C2-H2锌指组成的保守结构域。GLI3突变与小鼠突变体多趾以及人类的Greig头多指综合征和常染色体显性形式的Pallister-Hall综合征有关。因此，GLI和脊椎动物刺猬信号通路/ patched信号通路似乎在正常发育和肿瘤形成中都发挥着重要作用。
由于尚不清楚异常的GLI表达是否同样与发育障碍有关，我们构建了功能获得性转基因小鼠，使其异位表达人类GLI。
受影响的转基因小鼠表现出发育不良、过早死亡以及类似先天性巨结肠的胃肠道扩张斑块的表型。受影响小鼠的结肠平滑肌层明显变薄，上皮细胞异常。结肠壁中肌间神经丛的密度降低。表型的严重程度与转基因表达水平相关。
转基因小鼠模型支持GLI在胃肠道发育中发挥作用。作为脊椎动物刺猬信号通路/ patched信号通路的一部分，GLI对中胚层和中枢神经系统外胚层发育至关重要，并影响肠道中的神经元、肌肉和上皮细胞分化。在小鼠中表达人类GLI会导致肠道神经元发育受损并出现类似先天性巨结肠的表型。
