美国St.Jude儿童研究医院的研究者以老鼠为实验模式，发现在哺乳类胚胎发育过程中，Six3基因是最早开始控制眼球形成晶状体的关键基因。这项发现发表于本周的《欧洲分子生物学组织》（The EMBO Journal）期刊中。
??根据前期研究，Six3基因突变或异常会导致人类脑部发育最常见的前脑发育畸形症（holoprosencephaly）。该病导致病人的端脑与脑间的大脑不能正常分成两个浅裂片。
??几年前，St.Jude研究小组研究证明，Six3活性在小鼠前脑发育过程中起着关键作用。
??目前，St.Jude研究人员通过研究，指出Six3会直接活化眼睛发育的重要基因Pax6，进而启动一系列晶状体发育需要的基因。在Six3基因突变体中，Pax6不能调控与晶状体（Lens）有关的一系列其他基因。
英文原文：
Key gene controlling eye lens development identified
Investigators at St. Jude Children's Research Hospital have discovered in mouse models that a gene called Six3 is one of the earliest critical regulators controlling lens development in the eye of the mammalian embryo.
Mutations in Six3 have been previously identified in patients with holoprosencephaly, a disease that can cause the part of the brain called the cerebrum to fail to divide normally into two lobes. Holoprosencephaly is the most common abnormality of the development of the forebrain (front part of the brain) in humans. A few years ago the St. Jude team demonstrated that Six3 activity is critical for the normal development of the forebrain in mice.
St. Jude researchers have now extended these results by showing in the developing eye that Six3 normally exerts its effect by directly activating Pax6, a gene considered the "master regulator of eye development." In the absence of Six3, Pax6 fails to coordinate the activity of a series of additional genes that cooperate to form the lens. A report on this work appears in the prepublication online issue of The EMBO Journal.
Previously, the researchers were not able to address the gene's possible role in mouse eye formation because inactivation of Six3 significantly disrupted development of the area of the brain where the eye normally forms. The St. Jude team overcame this problem by taking advantage of Cre/loxP-technology, which allowed them to choose the time and place in which to remove Six3 function from specific cells. This permitted the investigators to remove Six3 activity from the presumptive lens ectoderm (PLE)--the area of the developing head where the lens will ultimately form in response to a series of biochemical signals. Following this systematic approach, the St. Jude team demonstrated that Six3 plays its important role in the PLE. The investigators also showed that a key consequence of removing Six3 during early development is that the PLE fails to undergo its normal thickening, an initial critical step in lens formation.
"Our discovery helps to better unravel the regulatory pathway that controls normal lens formation," said the paper's senior author, Guillermo Oliver, Ph.D., a member of the St. Jude Genetics and Tumor Cell Biology department. "Specifically, it puts the Six3 gene at the top of the genetic cascade that controls the development of the lens. Understanding the early steps leading to lens formation will help us determine what goes wrong in disorders in which the lens does not form, or forms abnormally. That kind of information is often the first step in designing both preventive and treatment strategies for congenital diseases."
The St. Jude team further showed that the proteins coded for by Six3 are present in the PLE before those coded by Pax6. This was evidence that production of Pax6 proteins in that region of the head starts after Six3 proteins are made, further supporting the idea that the Six3 gene controls the Pax6 gene. The researchers also demonstrated that the Six3 protein directly controls the expression of the Pax6 gene by binding to some of the DNA regions that regulate Pax6 activity.
"Our work confirms the early and vital role Six3 plays in the overall development of the eye, and gives us important insights into the interplay of genes during this time," said Wei Liu, Ph.D., a postdoctoral fellow in Oliver's laboratory. Lui is first author of the paper.
