Repression of Non-Ocular Fates by the SIX and EYA Genes During Specification and Patterning of the Retina

 描述（由申请方提供）：器官/组织鉴别的质量标准是动物发育的基本要求，因为必须以正确的数量制备每种组织/器官类型，放置在正确的位置，并构建为正常发挥功能。对这一过程的传统观点是，基因调控网络的功能完全是为了促进预期的命运。然而，越来越多的证据，包括我的研究小组的几项发现，强烈表明器官和组织身份的确定实际上有两个要求：1）指定所需的组织和2）抑制替代命运。这种范式转换模型可能特别有价值的情况是在不同组织类型之间建立边界。在这方面，眼睛发育提供了一个理想的机会来测试我们的组织规格的新模型。在果蝇中，几个非眼结构，如头部表皮，触角和下颚须边缘发育苍蝇视网膜。我们检查了无眼（so）和无眼（eya）突变视网膜，并确定了在周围非眼组织中正常表达的选择基因在眼区被异位激活。这些因子在视网膜祖细胞中的激活迫使眼区向表皮组织的同源异型转化。脊椎动物的眼睛同样起源于与非眼组织（包括端脑、间脑和下丘脑）接壤的区域。最近的研究表明，几个选择基因控制他们的发展也异位激活的眼睛Lhx 2和青蛙rax突变体。在脊椎动物和苍蝇中看到的转化表明，眼和非眼命运的分离对于正确的头部和眼睛的形成至关重要。本提案的目的是确定Sine Oculis Homeobox（SIX）和Eyes Absent（EYA）蛋白如何通过抑制发育中视网膜中的非眼命运来促进眼睛形成。拟议研究的基本原理是，所选择的问题集中在可能高度保守的过程，从而使果蝇的研究揭示组织/器官形成的一般机制。令人兴奋的初步数据指导了以下具体目标：（1）研究SIX/EYA蛋白在眼睛特化期间对非眼命运的新抑制中所起的作用;（2）测试通过形态发生沟的视网膜图案化需要通过Dpp信号传导和SIX/EYA蛋白抑制非眼命运的假设;和（3）鉴定Eya表达在眼区域中被激活和在邻近的非眼组织中被抑制的分子机制。拟议的研究测试创新的假设，是重要的，因为我们的结果将揭示新的影响深远的原则，管理组织/器官的规格和模式。这项工作也将进一步了解这些过程中的错误如何促进先天性疾病的诱导。

 DESCRIPTION (provided by applicant): Specification of organ/tissue identity is a fundamental requirement of animal development as it is imperative that each tissue/organ type be made in the right numbers, placed in the right location and constructed to function properly. The traditional view of this process has been that gene regulatory networks function exclusively to promote the desired fate. However, a growing body of evidence, including several discoveries from my research group, strongly suggests that determination of organ and tissue identity actually has two requirements: 1) specifying the desired tissue and 2) repressing alternate fates. A situation where this paradigm-shifting model is likely to be particularly valuable is in establishing boundaries between distinct tissue types. In this respect eye development provides an ideal opportunity to test our new models of tissue specification. In Drosophila, several non-ocular structures such as the head epidermis, antenna, and maxillary palp border the developing fly retina. We examined sine oculis (so) and eyes absent (eya) mutant retinas and have determined that selector genes normally expressed in the surrounding non-ocular tissues are ectopically activated in the eye field. Activation of these factors within retinal progenitor clls forces a homeotic transformation of the eye field into epidermal tissue. The vertebrate eye similarly arises from a territory that is bordered by non-ocular tissues including the telencephalon, diencephalon, and hypothalamus. Recent studies have shown that several selector genes controlling their development are also ectopically activated in the eyes of mouse Lhx2 and frog rax mutants. The transformations that are seen in both vertebrates and flies indicate that segregation of ocular and non-ocular fates is essential for proper head and eye formation. The objective of this proposal is to determine how Sine Oculis Homeobox (SIX) and Eyes Absent (EYA) proteins promote eye formation by repressing non-ocular fates in the developing retina. The rationale for the proposed research is that the chosen questions are focused on processes that are likely to be highly conserved, thereby allowing studies in Drosophila to uncover general mechanisms of tissue/organ formation. Exciting preliminary data guides the following specific aims: (1) Investigate the role that SIX/EYA proteins play in the novel suppression of non-ocular fates during eye specification; (2) Test the hypothesis that retinal patterning by the morphogenetic furrow requires suppression of non-ocular fates by Dpp signaling and SIX/EYA proteins; and (3) Identify the molecular mechanism by which eya expression is activated in the eye field and repressed in bordering non-ocular tissues. The proposed studies test innovative hypotheses and are significant because our results will uncover new far-reaching principles governing tissue/organ specification and patterning. The work also will further our understanding of how errors in these processes facilitate the induction of congenital disorders.