Regulation of the DYRK1A kinase by the Down Syndrome Cell Adhesion Molecule DSCAM

唐氏综合症细胞粘附分子 DSCAM 对 DYRK1A 激酶的调节

• 批准号: 10573072
• 负责人: PETER Gerard FUERST
• 金额: $ 15万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2023-02-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10573072
• 关键词: Address; Affect; Aneuploidy; Area; Axon; Biochemical; Biological Assay; Blindness; Brain; Brain region; Cell Adhesion Molecules; Cell Death; Cell Nucleus; Cell Surface Receptors; Cell surface; Cellular biology; Cerebellum; Chromosome 16; Chromosome 21; Clinical; Cues; Cytoplasmic Tail; Data; Defect; Dendrites; Development; Disease; Down Syndrome; Down Syndrome Cell Adhesion Molecule; Environment; Event; Eye; Foundations; Future; Gene Duplication; Gene Expression; Genes; Genetic; Genetic study; Goals; Hippocampus (Brain); Human Chromosomes; Idaho; In Vitro; Intervention; Knowledge; Link; Mediating; Modeling; Molecular; Morphology; Mosaicism; Mus; Mutation; Nervous system structure; Neurites; Neurons; Neurophysiology - biologic function; Nuclear; Nuclear Translocation; Organ; Outcome; Pathology; Persons; Phenocopy; Phenotype; Phosphotransferases; Pilot Projects; Play; Population; Proteins; Publications; Reagent; Regulation; Reporting; Research; Research Proposals; Retina; Role; Schizophrenia; Scientist; Signal Pathway; Signal Transduction; Signaling Molecule; Signs and Symptoms; Specificity; Surface; Syndrome; System; Testing; Time; Tissues; Tyrosine Phosphorylation; Universities; Work; autism spectrum disorder; base; cell type; dosage; experience; experimental study; gain of function; human disease; loss of function; mouse Ts65Dn; mouse model; neurodevelopment; novel; overexpression; postnatal; prevent; receptor; relating to nervous system; response; retinal neuron

ABSTRACT: Candidate and Environment: The Fuerst Lab will conduct genetic, molecular and morphological experiments related to the Aims of this proposal at the University of Idaho. The Fuerst lab team has extensive expertise centered on the cell biology and genetics of neural development. Fuerst identified Dscams as the first molecules that regulate mosaic organization of neurons and developed many of the genetic reagents for use in these experiments. Here we will build on our foundation of experience studying Dscam genes to probe the function of downstream signaling networks in neural development. Research Proposal: Developing neurons utilize a range of molecular cues to organize into neural tissues and organs. We and others have previously reported that Down syndrome cell adhesion molecule (Dscam) genes are required for normal development of neural tissues. How Dscam genes mediate a wide range of cellular responses even within a single cell type is an active area of research. In our preliminary studies we found that overexpression of Dyrk1a, whose product interacts biochemically with DSCAM, phenocopies Dscam loss of function. Further we report a redistribution of cellular DYRK1A protein in the Dscam loss of function retina and brain. Based on these observations and the genes’ known antagonistic roles in either promoting or inhibiting developmental cell death, we hypothesize that DSCAM interactions on the cell surface antagonize DYRK1A activity by controlling its subcellular localization. We test this hypothesis in two specific Aims. Aim 1: Pilot genetic studies indicate that either decreasing Dscam dosage or increasing Dyrk1a dosage results in mistargeting of retinal neuron neurites. A similar increase in Dyrk1a expression in the Ts65Dn trisomic mouse models results in a wild type targeting phenotype, however, suggesting a factor or factors in the Down syndrome critical region (DSCR) are compensating for Dyrk1a overexpression. First, we will test if increasing Dyrk1a expression in the Ts65Dn mouse model above the expression of other DSCR genes is sufficient to restore Dyrk1a overexpression neurite targeting defects (Aim 1A). Second, we will test if reducing Dscam expression in Ts65Dn mice to wild type levels restores the Dyrk1a overexpression phenotype (Aim 1B). Aim 2: We will extend our pilot study generated in retina into the brain at large. We will test if DYRK1A localization is developmentally dynamic in the brain (Aim 2A), if DSCAM regulates DYRK1A localization in the brain (Aim 2B) and if Dscam expression is sufficient to modify DYRK1A accumulation or localization in vitro (Aim 2C). Long-term goals: Our long-term goal is to understand how events at the cell surface are transduced to generate different cellular responses. This R03 will facilitate completion and publication of a pilot study, the results of which will inform experiments to understand how regulation of DYRK1A localization impacts its function in development and disease. Significance: Understanding why mutation or overexpression of genes involved in neural development can present with a variety of signs and symptoms in people will require us to also understand the functions of the affected genes with the long-term goal of developing clinical interventions. Here we explore the interaction between two interacting genes in the Down Syndrome critical region, relevant to studies and treatments focusing on either single gene. Understanding the downstream signaling pathways utilized by surface receptors will be essential to help scientists and clinicians pinpoint strategies to treat human diseases.

摘要：候选人与环境：福斯特实验室将进行遗传，分子和形态肠细胞 与此提案在爱达荷大学的目标相关的经验。 专业知识集中于细胞生物学和神经发育的遗传学。 调节神经元的镶嵌组织并开发了许多遗传试剂的分子 这些实验。 下游信号网络在神经发展中的功能。 利用一系列分子提示来组织神经组织和器官。 报道唐氏综合征细胞粘附分子（DSCAM）基因需要形式发展 神经组织DSCAM基因如何介导广泛的细胞反应 在我们的预序研究中，我们发现Dyrk1a的过表达 与DSCAM，表型DSCAM功能丧失的生化相互作用。 基于观测值的DSCAM功能视网膜和大脑的细胞dyrk1a蛋白质。 基因在促进或抑制发育细胞死亡中已知的拮抗作用，我们假设 DSCAM在细胞表面上的相互作用通过控制其亚细胞来拮抗DyRK1a活性 本地化。 降低DSCAM剂量或增加DYRK1A剂量会导致视网膜神经突扰动。 TS65DN Trisomic小鼠模型中DYRK1A表达的类似增加导致野生型靶向 表型，霍弗（Howver），暗示唐氏综合症关键区域（DSCR）中的一个因素是 补偿DYRK1A的过表达，我们将测试是否增加了TS65DN中的DYRK1A 鼠标模型上方的DSCR基因的表达高度足以恢复DYRK1A过表达 神经突的靶向缺陷（AIM 1A）。 类型级别resters dyrk1a过表达表型（AIM 1B）。 在视网膜中产生的大脑。 大脑（AIM 2A），如果DSCAM调节大脑中的DYRK1A定位（AIM 2B），并且DSCAM表达为 足以在体外改变DYRK1A的积累或定位（AIM 2C）。 长期目标：我们的长期目标是了解细胞表面的事件是如何转导的 产生不同的细胞反应。 哪些WILLM实验的结果了解DYRK1A定位的调节如何影响IST 发育和疾病的功能。 意义：了解为什么与神经发育有关的基因突变或过表达 可以在患有患者的人中表现出各种迹象和症状，要求我们也了解 受影响的基因具有开发临床国际的长期目标。 唐氏综合症关键区域的两个相互作用基因之间与研究和治疗有关 专注于任何一个基因。 受体遗嘱对于帮助科学家和临床医生确定信任人类疾病的策略至关重要。