Retinoid Dehydrogenases Involved in Eye Development

类视黄醇脱氢酶参与眼睛发育

基本信息

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
项目类别：
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

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

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项目摘要

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，可作为信号分子。 RA对于眼睛发育至关重要，但其作用知之甚少。当将视黄醇代谢为RA时，将发生RA信号传导，RA（作为调节基因表达的核RA受体的配体）。控制胚胎发生过程中RA合成的酶正在研究中，此类研究正在提供有关眼睛发育过程中RA作用机理的新信息。对小鼠胚胎的研究表明，在综合Ra（即RaldH1，RaldH2和RaldH3）中差异表达的三种视网膜脱水酶存在。 RALDH1，RALDH2和RALDH3 NULL突变小鼠的调查具有发现的眼睛缺陷，对这些小鼠的进一步研究开始揭示RA作用的机制。由于三个RALDH基因在小鼠和人类中是保守的，因此我们开发的空突变体是理解人眼发育过程中RA作用机制的出色小鼠模型。有证据表明，由饮食中维生素A缺乏症引起的RA缺乏可能与称为眼分离的人眼缺陷有关。提出的遗传研究将提供与人眼疾病的治疗有关的信息，其病因涉及RA合成和/或饮食中维生素A缺乏症的遗传缺乏：我们发现，RA合成的位置在眼睛发育过程中经历了动态时空变化，并且RA CAPITION在同步中的位置会发生变化。 raldh2/raldh3双突变小鼠胚胎会形成视囊，但是该结构缺乏RA合成，并且未能腹侧凹陷以形成光学杯。 RALDH3无效突变体胚胎会产生一个光学杯，但它们显示出闭合视神经裂（Coloboma）的缺陷。 Raldhl无效突变胚胎在背视网膜中缺乏RA合成，但未观察到眼缺陷。然而，Raldh1/Raldh3双突变体显示出在视网膜前方的围栏间充质的过度侵袭，从而揭示了RALDHL的功能，通常由Raldh3（且反之亦然）补偿。这些发现导致了这样的假设，即RA控制着眼睛形态发生运动，而不是如前所述的视网膜背腹形图。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，尤其是EY中RA调节的基因网络。我们将检验以下假设，即RA调节视网膜和周围的围栏间充质的眼睛形态发生运动。这些研究将使用未通过各种遗传或药理方法验证或挽救的RALDH化合物零突变小鼠进行基因进行。具体研究将重点放在：（1）在视觉杯形成过程中对细胞形状和细胞粘附的控制；（2）视杯形成期间的RA-FGF拮抗作用；（3）在视觉杯形成后，RA控制毛细胞间充质入侵。