Retinoid Dehydrogenases Involved in Eye Development

类视黄醇脱氢酶参与眼睛发育

• 批准号: 7303907
• 负责人: GREGG L DUESTER
• 金额: $ 47.75万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7303907
• 关键词: ALDH1A2 gene; Address; All-Trans-Retinol; Alleles; Anterior; Apoptosis; Apoptotic; Cell Adhesion; Cell Shape; Cell division; Closure; Coloboma; Confocal Microscopy; Cornea; Defect; Dorsal; Electrons; Embryo; Embryonic Development; Enzymes; Etiology; Exhibits; Eye; Eye Development; Eye diseases; Eyelid structure; FGF8 gene; Fibroblast Growth Factor; Fibroblast Growth Factor 8; Fibroblast Growth Factor Receptors; Gene Expression; Genes; Genetic; Goals; Human; Investigation; Ligands; Link; Location; Mesenchymal; Mesenchyme; Messenger RNA; Metabolic; Methods; Microscopic; Movement; Mus; Mutant Strains Mice; Neural Retina; Nuclear; Optic vesicle; Optics; Oxidoreductase; Pattern; Proteins; Publishing; RalDH1; Range; Regulation of Cell Shape; Reporter; Retina; Retinal; Retinoic Acid Receptor; Retinoids; Signal Transduction; Signaling Molecule; Staging; Structure; Structure of retinal pigment epithelium; Testing; Thinking; Tissues; Transgenes; Tretinoin; Vitamin A; Vitamin A Deficiency; aldehyde dehydrogenase 1A2; autocrine; base; cellular retinoic acid binding protein; embryo culture; mouse model; mutant; null mutation; optic cup; paracrine; prevent; relating to nervous system; retinaldehyde dehydrogenase; spatiotemporal

DESCRIPTION (provided by applicant): Retinoic acid (RA) is a metabolic derivative of vitamin A (retinol) that functions as a signaling molecule. RA is essential for eye development, but its action is poorly understood. RA signaling occurs when retinol is metabolized to RA which serves as a ligand for nuclear RA receptors that regulate gene expression. The enzymes controlling synthesis of RA during embryogenesis are now under investigation and such studies are providing new information on the mechanism of RA action during eye development. Studies on mouse embryos have demonstrated the existence of three retinaldehyde dehydrogenases differentially expressed in the eye that synthesize RA, i.e. RALDH1, RALDH2, and RALDH3. Investigations of Raldh1, Raldh2, and Raldh3 null mutant mice have uncovered eye defects, and further studies of these mice are beginning to reveal the mechanism of RA action. As the three Raldh genes are conserved in mice and humans, the null mutants we have developed are excellent mouse models for understanding the mechanism of RA action during human eye development. Evidence exists suggesting that RA deficiency caused by dietary vitamin A deficiency may be linked to the human eye defect known as ocular coloboma. The genetic studies proposed will provide information relevant to treatment of human eye diseases whose etiology involves genetic deficiency in RA synthesis and/or dietary vitamin A deficiency: We have found that the location of RA synthesis undergoes dynamic spatiotemporal changes during eye development, and that the location of RA action changes in synchrony. Raldh2/Raldh3 double mutant mouse embryos develop an optic vesicle, but this structure lacks RA synthesis and fails to invaginate ventrally to form the optic cup. Raldh3 null mutant embryos develop an optic cup but they display defects in closure of the optic fissure (coloboma). Raldhl null mutant embryos lack RA synthesis in the dorsal retina, but eye defects are not observed. However, Raldh1/Raldh3 double mutants display excessive invasion of perioptic mesenchyme anterior to the retina, thus revealing a function for Raldhl that is normally compensated by Raldh3 (and vice-versa). These findings have led to the hypothesis that RA controls eye morphogenetic movements rather than dorsoventral patterning of the retina as previously thought. The overall goal of this project is to determine the mechanism of RA signaling during eye development, particularly the gene networks regulated by RA in the eye. We will test the hypothesis that RA regulates eye morphogenetic movements of both the retina and the surrounding perioptic mesenchyme. These studies will be performed genetically using Raldh compound null mutant mice that are unrescued or rescued by various genetic or pharmacological methods. Specific investigations will focus upon: (1) RA control of cell shape and cell adhesion during optic cup formation; (2) RA-FGF antagonism during optic cup formation; (3) RA control of perioptic mesenchyme invasion following optic cup formation.

描述（由申请人提供）：视黄酸（RA）是维生素A（视黄醇）的代谢衍生物，作为信号分子发挥作用。RA对眼睛发育至关重要，但其作用知之甚少。当视黄醇代谢为RA时，RA信号传导发生，RA作为调节基因表达的核RA受体的配体。目前正在研究胚胎发育过程中控制RA合成的酶，这些研究为RA在眼发育过程中的作用机制提供了新的信息。对小鼠胚胎的研究表明，存在三种在眼睛中差异表达的合成RA的视黄醇脱氢酶，即RALDH 1、RALDH 2和RALDH 3。对Raldh 1、Raldh 2和Raldh 3无效突变小鼠的研究发现了眼睛缺陷，对这些小鼠的进一步研究开始揭示RA作用的机制。由于这三个Raldh基因在小鼠和人类中是保守的，因此我们开发的无效突变体是用于理解RA在人眼发育过程中的作用机制的极好的小鼠模型。有证据表明，由膳食维生素A缺乏引起的RA缺乏症可能与称为眼缺损的人眼缺陷有关。建议的遗传学研究将提供相关的人类眼病的病因涉及RA合成和/或饮食中的维生素A缺乏症的遗传缺陷的治疗信息：我们已经发现，RA合成的位置经历动态时空变化在眼睛发育过程中，和RA行动的位置同步变化。Raldh 2/Raldh 3双突变小鼠胚胎发育成视泡，但这种结构缺乏RA合成，并且未能向腹侧内陷以形成视杯。Raldh 3无效突变胚胎发育出视杯，但它们表现出视裂闭合缺陷（缺损）。Raldhl无效突变胚胎缺乏RA合成的背侧视网膜，但没有观察到眼睛缺陷。然而，Raldh 1/Raldh 3双突变体显示过度侵入视网膜前的视周间充质，从而揭示了Raldh 1的功能，该功能通常由Raldh 3补偿（反之亦然）。这些发现导致了一种假设，即RA控制眼睛形态发生运动，而不是像以前认为的那样控制视网膜的背腹图案。该项目的总体目标是确定眼睛发育过程中RA信号传导的机制，特别是眼睛中由RA调控的基因网络。我们将测试的假设，RA调节眼睛的视网膜和周围的视周间充质的形态发生运动。这些研究将使用未获救或通过各种遗传或药理学方法获救的Raldh化合物无效突变小鼠进行遗传学研究。具体的研究将集中在：（1）视杯形成过程中RA对细胞形状和细胞粘附的控制;（2）视杯形成过程中RA-FGF拮抗作用;（3）视杯形成后RA对视周间充质浸润的控制。