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

视网膜规范和图案化过程中 SIX 和 EYA 基因对非眼命运的抑制

• 批准号: 9135417
• 负责人: Justin P Kumar
• 金额: $ 39.06万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135417
• 关键词: Affect; Animal Model; Animals; Characteristics; Chickens; Congenital Disorders; Data; Defect; Development; Drosophila genus; Drosophila melanogaster; Epidermis; Erinaceidae; Event; Eye; Eye Development; Failure; Gene Family; Genes; Growth; Head; Health; Histocompatibility Testing; Homeobox; Homeostasis; Human; Hypothalamic structure; Location; Maintenance; Maxilla; Modeling; Molecular; Mus; Organ; Pattern; Phenotype; Play; Process; Proteins; Public Health; Rana; Regulator Genes; Repression; Research; Research Design; Retina; Retinal; Role; Second Look Surgery; Signal Transduction; Specific qualifier value; Structure; System; Telencephalon; Testing; Thalamic structure; Tissue Model; Tissues; To specify; Vertebrates; Visual Fields; Work; Zebrafish; diencephalon; eye formation; fly; gain of function; innovation; loss of function; loss of function mutation; mutant; novel; prevent; programs; retinal progenitor cell; segregation; tumor

 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.

 描述（由申请人提供）：器官/组织特性的规范是动物发育的基本要求，因为每种组织/器官类型必须以正确的数量制成，放置在正确的位置并构建为正常运行。对于这一过程的传统观点是，基因调控网络专门发挥促进预期命运的作用。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，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界限。在这方面，眼睛发育为测试我们的新组织规范模型提供了理想的机会。在果蝇中，一些非眼部结构，如头部表皮、触角和上颌须，与发育中的果蝇视网膜接壤。我们检查了正弦眼 (so) 和缺眼 (eya) 突变视网膜，并确定通常在周围非眼组织中表达的选择基因在眼区域异位激活。视网膜祖细胞内这些因子的激活迫使眼区同源转化为表皮组织。脊椎动物的眼睛同样起源于以非眼组织为边界的区域，包括端脑、间脑和下丘脑。最近的研究表明，一些控制其发育的选择基因在小鼠 Lhx2 和青蛙 rax 突变体的眼睛中也被异位激活。在脊椎动物和果蝇中观察到的转变表明，眼部和非眼部命运的分离对于头部和眼睛的正常形成至关重要。该提案的目的是确定正弦眼同源框 (SIX) 和眼睛缺失 (EYA) 蛋白如何通过抑制发育中视网膜的非眼命运来促进眼睛形成。拟议研究的基本原理是，所选问题集中于可能高度保守的过程，从而使果蝇研究能够揭示组织/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 蛋白在眼睛规范过程中对非眼命运的新型抑制中所发挥的作用； (2) 检验以下假设：形态发生沟形成的视网膜图案需要通过 Dpp 信号传导和 SIX/EYA 蛋白抑制非眼命运； (3) 确定 eya 表达在眼部区域被激活并在非眼部边缘组织中被抑制的分子机制。拟议的研究测试了创新的假设，并且意义重大，因为我们的结果将揭示管理组织/器官规范和模式的新的影响深远的原则。这项工作还将进一步加深我们对这些过程中的错误如何促进先天性疾病的诱发的理解。