Mutually regulated expression of Pax6 and SW and its implications for the Pax6 haploinsufficient lens phenotype
Mutually regulated expression of Pax6 and SW and its implications for the Pax6 haploinsufficient lens phenotype
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DOI：
10.1073/pnas.132195699
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发表时间：
2002-06-25
影响因子：
11.1
通讯作者：
Gruss, P
中科院分区：
文献类型：
--
作者：
Goudreau, G;Petrou, P;Gruss, P
Pax 6是脊椎动物和无脊椎动物眼睛发育的关键调节因子，小鼠Pax 6基因的杂合功能丧失突变导致小眼表型，其中小透镜是恒定特征。为了了解这种单倍不足表型的机制，我们在Pax 6杂合子小鼠中评估了减少Pax 6基因剂量对调节眼睛形成的其他转录因子活性的影响。我们发现Six 3表达在Pax 6杂合子小鼠胚胎的晶状体中特异性降低。在果蝇和脊椎动物中已经鉴定了来自Pax和Six家族的正向基因之间的相互作用，并且我们检查了发育中的小鼠透镜中的Pax 6和Six 3基因表达的控制。使用体外和转基因的方法，我们发现，无论是转录因子结合从对应的基因的调控序列，这两个基因相互激活其表达。这些研究定义了透镜中的功能关系，其中Six 3表达与Pax 6呈剂量依赖性，相反，Six 3激活Pax 6。因此，我们在转基因小鼠中晶状体特异性表达Six 3后显示了Pax 6单倍不足透镜表型的拯救。这种表型拯救伴随着细胞增殖和血小板衍生生长因子α-R/细胞周期蛋白D1信号通路的激活。因此，我们的研究结果提供了一种机制，涉及Pax 6和Six 3之间的基因调控相互作用的组织特异性缺陷中发现的Pax 6杂合子小鼠。
Pax6 is a key regulator of eye development in vertebrates and invertebrates, and heterozygous loss-of-function mutations of the mouse Pax6 gene result in the Small eye phenotype, in which a small lens is a constant feature. To provide an understanding of the mechanisms underlying this haploinsufficient phenotype, we evaluated in Pax6 heterozygous mice the effects of reduced Pax6 gene dosage on the activity of other transcription factors regulating eye formation. We found that Six3 expression was specifically reduced in lenses of Pax6 heterozygous mouse embryos. Interactions between orthologous genes from the Pax and Six families have been identified in Drosophila and vertebrate species, and we examined the control of Pax6 and Six3 gene expression in the developing mouse lens. Using in vitro and transgenic approaches, we found that either transcription factor binds regulatory sequences from the counterpart gene and that both genes mutually activate their expression. These studies define a functional relationship in the lens in which Six3 expression is dosage-dependent on Pax6 and where, conversely, Six3 activates Pax6. Accordingly, we show a rescue of the Pax6 haploinsufficient lens phenotype after lens-specific expression of Six3 in transgenic mice. This phenotypic rescue was accompanied by cell proliferation and activation of the platelet-derived growth factor alpha-R/cyclin D1 signaling pathway. Our findings thus provide a mechanism implicating gene regulatory interactions between Pax6 and Six3 in the tissue-specific defects found in Pax6 heterozygous mice.