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Patterning Genes in Retinal Development

视网膜发育中的模式基因

基本信息

批准号：
10334463
负责人：
Deborah L Stenkamp
金额：
$ 35.64万
依托单位：
UNIVERSITY OF IDAHO
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10334463
关键词：
3-Dimensional Affect Age related macular degeneration Cells Clinic Collaborations Color Visions Color blindness Communities Cone Data Defect Development Disease Event Exons Eye diseases Functional disorder Future Gene Expression Generations Genes Genetic Genome Goals Grant Heritability Human Human X Chromosome Image Immersion In Vitro Injury Knowledge Lead Link Mammals Measurement Mediating Methods Modeling Molecular Myopia Natural regeneration Nuclear Receptors Nucleic Acid Regulatory Sequences Opsin Organoids Pattern Pharmacology Phenotype Photoreceptors Population Primates Process Public Health Publishing Receptor Signaling Regenerative Medicine Regulation Retina Retinal Cone Retinal Degeneration Retinal Diseases Retinal Pigments Retinoids Role Sampling Series Signal Transduction Signaling Molecule Stargardt&apos s disease Therapeutic Thyroid Hormones Transplantation Tretinoin Vertebrates X Chromosome Zebrafish analog base cell replacement therapy cell type differential expression differentiation protocol embryo stage 2 gain of function genetic manipulation genetic resource human stem cells in vivo in vivo evaluation induced pluripotent stem cell insight loss of function novel paralogous gene progenitor promoter receptor regenerative regenerative approach response retinal regeneration sensory system small molecule teleost fish transcriptome translational applications vision science

项目摘要

Patterning Genes in Retinal Development – Project Summary The long-range goal of this grant is to determine the cellular and molecular events that lead to the generation of specific cell types in the vertebrate retina. In this renewal we focus upon mechanisms regulating differential expression of the cone visual pigment genes on tandemly-replicated gene arrays. In humans a tandemly-replicated array on the X chromosome consists of one long wavelength-sensitive (LWS) gene followed by 1-9 medium wavelength-sensitive (MWS) genes, which have diverged spectrally from LWS. This recent replication has provided most humans with trichromatic color vision, because LWS, MWS, and SWS1 opsins are uniquely expressed in separate cone populations. Heritable defects in the LWS/MWS array result in various forms of color blindness, X-linked retinal degenerations, and Bornholm Eye Disease, a cone dysfunction associated with high myopia. Insights into regulation of differential expression of LWS vs. MWS opsins could allow therapeutic manipulation of gene expression to treat these disorders. In addition, future regenerative approaches to the treatment of other retinal disorders that involve the loss of cones (age-related macular degeneration; Stargardt’s disease) would ideally include similar in vitro or in vivo manipulations to generate cone phenotypes in ratios that support high-acuity color vision. The widely-accepted model for human LWS vs. MWS opsin regulation states that a stochastic event favors an association of an upstream regulatory region with the LWS or most proximal MWS. However, topographic patterns of the LWS:MWS ratio suggest that a nonrandom, trans regulatory mechanism may be involved. Pursuit of regulatory mechanisms has been challenging because within mammals, only primate genomes contain tandem opsin arrays. In contrast, the genomes of teleost fish, including zebrafish, contain numerous tandem arrays of opsins, which are the consequences of independent gene replication events and neofunctionalization. In our published and preliminary data we demonstrate that in zebrafish, the developmental signaling molecules retinoic acid (RA), and thyroid hormone (T3) can each control differential expression of the tandem duplicates, LWS1 vs. LWS2, an array orthologous to the human LWS/MWS array. Furthermore, compelling preliminary data suggest that RA can promote expression of LWS opsin in human iPSC-derived 3D retinal organoids, changing the ratio of LWS:MWS. Together these findings lay the groundwork for a tremendous breakthrough in understanding determination of LWS vs. MWS cone subtype. In this renewal we pursue mechanisms through which RA and T3 control differential expression of tandemly replicated opsins, and apply this knowledge to retinal regeneration and human retinal organoid development, with three Specific Aims: 1. Determine the relative roles of RA and T3 signaling and their receptors as endogenous regulators of differential expression of tandemly replicated opsin genes. 2. Determine mechanisms through which RA and T3 signaling regulate tandemly replicated opsin genes. 3. Determine roles of RA and T3 signaling for controlling cone fates during retinal regeneration and in human iPSC-derived 3D retinal organoids. These studies will uncover novel mechanisms for the differential expression of tandemly replicated opsin genes, and will generate information necessary to manipulate cone phenotypic fates in concert with the application of regenerative or cell replacement therapies for human retinal degenerations.

视网膜发育中的模式基因——项目摘要这笔赠款的长期目标是确定导致该现象的细胞和分子事件脊椎动物视网膜中特定细胞类型的产生。在这次更新中，我们重点关注调节机制串联复制基因阵列上视锥视觉色素基因的差异表达。在人类中 X 染色体上的串联复制阵列由一个长波长敏感 (LWS) 基因组成其次是 1-9 个中波长敏感 (MWS) 基因，它们在光谱上与 LWS 有所不同。这最近的复制为大多数人类提供了三色视觉，因为 LWS、MWS 和 SWS1 视蛋白在不同的视锥细胞群体中具有独特的表达。 LWS/MWS 阵列中的遗传缺陷导致各种形式的色盲、X连锁视网膜变性和博恩霍姆眼病（锥体病）与高度近视相关的功能障碍。深入了解 LWS 与 MWS 差异表达的调节视蛋白可以通过基因表达的治疗操作来治疗这些疾病。此外，未来治疗其他涉及视锥细胞丢失（与年龄相关）的视网膜疾病的再生方法黄斑变性； Stargardt 病）理想情况下包括类似的体外或体内操作以支持高敏锐色觉的比例生成视锥细胞表型。广泛接受的人类 LWS 与 MWS 视蛋白调节模型指出，随机事件有利于上游监管区域与 LWS 或最近的 MWS 的关联。然而， LWS:MWS 比率的地形模式表明，一种非随机的、反式的调节机制可能是涉及。对调节机制的探索一直具有挑战性，因为在哺乳动物中，只有灵长类动物基因组包含串联视蛋白阵列。相比之下，包括斑马鱼在内的硬骨鱼的基因组包含许多串联的视蛋白阵列，它们是独立基因复制事件的结果，新功能化。在我们发表的初步数据中，我们证明在斑马鱼中，发育信号分子视黄酸（RA）和甲状腺激素（T3）各自可以控制差异串联重复的表达，LWS1 与 LWS2，与人类 LWS/MWS 阵列直系同源的阵列。此外，令人信服的初步数据表明 RA 可以促进人类 LWS 视蛋白的表达 iPSC 衍生的 3D 视网膜类器官，改变了 LWS:MWS 的比例。这些发现共同表明为了解 LWS 与 MWS 锥体亚型的测定方面的巨大突破奠定了基础。在本次更新中，我们探索 RA 和 T3 控制差异表达的机制串联复制视蛋白，并将这些知识应用于视网膜再生和人类视网膜类器官开发，具有三个具体目标： 1. 确定 RA 和 T3 信号传导的相对作用及其受体作为串联复制视蛋白基因差异表达的内源调节因子。 2. 确定 RA 和 T3 信号传导调节串联复制视蛋白基因的机制。 3. 确定 RA 和 T3 信号传导在视网膜再生和人类视网膜再生过程中控制视锥细胞命运的作用 iPSC 衍生的 3D 视网膜类器官。这些研究将揭示差异表达的新机制串联复制的视蛋白基因，并将产生操纵视锥细胞表型所需的信息与人类视网膜再生或细胞替代疗法的应用相一致的命运退化。

项目成果

期刊论文数量（42）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cone mosaic development in the goldfish retina is independent of rod neurogenesis and differentiation

金鱼视网膜中的视锥细胞镶嵌发育独立于视杆神经发生和分化

DOI：
发表时间：
2000
期刊：
The Journal of comparative neurology
影响因子：
0
作者：
Jun Wan;D. L. Stenkamp
通讯作者：
D. L. Stenkamp

The interphotoreceptor retinoid-binding protein (IRBP) of the chicken (Gallus gallus domesticus).

鸡（Gallus gallus Domesticus）的光感受器间视黄醇结合蛋白（IRBP）。

DOI：
发表时间：
2005
期刊：
Molecular vision
影响因子：
2.2
作者：
Stenkamp,DeborahL;Calderwood,JohnL;VanNiel,EllenE;Daniels,LawrenceM;Gonzalez-Fernandez,Federico
通讯作者：
Gonzalez-Fernandez,Federico

Dynamic functional and structural remodeling during retinal regeneration in zebrafish.

DOI：
10.3389/fnmol.2022.1070509
发表时间：
2022
期刊：
FRONTIERS IN MOLECULAR NEUROSCIENCE
影响因子：
4.8
作者：
Barrett, Lindsey M.;Mitchell, Diana M.;Meighan, Peter C.;Varnum, Michael D.;Stenkamp, Deborah L.
通讯作者：
Stenkamp, Deborah L.

Ethanol-induced microphthalmia is not mediated by changes in retinoic acid or sonic hedgehog signaling during retinal neurogenesis.