Multiple steps in cell differentiaion : the case of lens development

头部外胚层需要Pax6活性才能对视神经囊泡的感应信号做出反应。Pax6表达在接下来的镜头开发中得到维护。当晶状体纤维和上皮分化时，Pax6在上皮间室的表达仍然很高，而在纤维间室的表达则降低，这表明Pax6在晶状体上皮中起着维持初级状态的第二个作用。鉴定参与晶状体诱导阶段的转录因子的一种方法是鉴定那些开启晶体蛋白基因的转录因子。在晶体蛋白基因中，鸡δ晶体蛋白似乎是最早表达的，从晶状体基板晚期开始表达。从鸡中克隆了一组与晶状体特异性基因内增强子中部结合的转录因子，这些转录因子对delta-crystallin基因的表达至关重要，它们分别是B组Sox蛋白Sox1、Sox1、so2和so3。紧接着视神经囊泡与头外胚层紧密接触的阶段，Sox2和Sox3在头外胚层的区域表达，这些区域与视神经囊泡接触的区域和产生晶状体位的区域完全对应。然后启动delta-crystallin基因表达，反映Sox2/3蛋白的作用。Sox1的表达开始稍晚，在晶状体发育后期成为主要的Sox蛋白。在小鼠晶状体中，Sox2的表达在晶状体诱导过程中被激活，但随着Sox1的激活，Sox2的表达很快被关闭。Sox1缺陷小鼠是通过靶向破坏该基因而产生的。在纯合子中，在Sox2被关闭的阶段，晶状体发育被阻止，γ -晶体蛋白表达减少，证实了Sox蛋白在晶状体发育和晶体蛋白基因激活中的重要功能。

Pax6 activity is required for the head ectoderm to have responsiveness to the inductive signal(s) of the optic vesicle. Pax6 expression is maintained in the following lens development. When the fibers and epithelia differentiate, Pax6 expression remains high in the epithelial compartment but decreases in the fiber compartment, suggesting its second role in the lens epithelium in maintaining the rudimentary state.An approach to identifying transcription factors involved in the stages following lens induction is to identify those which turn on crystallin genes. Among the crystallin genes, chicken delta-crystallin seems to be the earliest in its expression, starting from the late lens placode stage. A group of related transcription factors which bind to the middle of the lens-specific intragenic enhancer and are essential for the delta-crystallin gene expression were cloned from the chicken, and found to be Group B Sox proteins, Sox1, 2 and 3. Immediately following the stage of tight contact of the optic vesicle to the head ectoderm, Sox2 and Sox3 are expressed in regions of the head ectoderm which correspond exactly to those contacted by the optic vesicle and to those giving rise to the lens placode. Then, delta-crystallin gene expression is initiated reflecting the action of the Sox2/3 proteins. Sox1 expression starts slightly later, and becomes the major Sox protein in the later lens development. In the mouse lens also, Sox2 expression is activated during lens induction, but is soon turned off as Sox1 is activated. Sox1 deficient mice were produced by targeted disruption of the gene. In the homozygotes, lens development is arrested and gamma-crystallin expression is diminished at the stage at which Sox2 is turned off, confirming the essential function of Sox proteins in lens development and in crystallin gene activation.