Homeobox Gene Six3 in Forebrain and Visual System Development

描述（由申请人提供）：先天性视网膜异常，如视网膜退行性疾病，导致全世界数百万人不同程度的不可逆视力丧失。虽然我们对视网膜发育的理解的最新进展促进了使用筛查方案来检测与这些眼部疾病相关的基因突变，但还没有可用的治疗方法。一个保守的转录因子网络对于眼睛的形成是必不可少的。含有同源框的基因Six 3是调节视觉系统发育的复杂网络的成员之一。有条件地从发育中的小鼠视野中去除Six 3足以阻止NR特化;这一结果表明Six 3在脊椎动物视网膜发育过程中的关键作用。本申请中提出的工作建立在我们以前的发现和我们生成的小鼠模型的基础上，以扩展我们对导致视觉系统形成的过程的知识。 公共卫生相关性：使用胚胎干细胞（ESC）和诱导多能干细胞（iPSC）的最新进展表明，有一天细胞替代疗法将用于治疗这些眼部疾病。实现这一目标的先决条件是更好地理解控制正常视网膜发育的调节级联和信号通路。这些知识将帮助我们更好地了解眼部疾病的发病机制，并提供必要的框架来设计方法，这些方法将促进未来的努力，旨在控制ESC和iPSC在体内和体外分化为视网膜细胞。

DESCRIPTION (provided by applicant): Congenital retina abnormalities such as retinal degenerative diseases cause varying degrees of irreversible vision loss in millions of people worldwide. Although recent advances in our understanding of retinal development have facilitated the use of screening protocols to detect mutations in genes associated with those ocular diseases, no therapeutic approach is yet available. A conserved network of transcription factors is essential for eye formation. The homeobox-containing gene Six3 is one of the members of that complex network that regulates visual system development. Conditional removal of Six3 from the developing mouse eye field is sufficient to arrest NR specification; a result demonstrating the critical role of Six3 during vertebrate retina development. The work proposed in this application builds on our previous findings and our generated mouse models to expand our knowledge about the processes leading to the formation of the visual system. PUBLIC HEALTH RELEVANCE: Recent advances using embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) suggest that one day cell-replacement therapy will be used to treat these ocular diseases. A prerequisite to achieving this goal is to better understand the regulatory cascades and signaling pathways that control normal retina development. This knowledge will help us to better understand the pathogenesis of ocular diseases and provide the essential framework necessary to design approaches that will facilitate future efforts aimed toward controlling the differentiation of ESCs and iPSCs, in vivo and in vitro, into retina cells.