22q11 Genes and Complex Behavior in Mice

22q11 基因和小鼠的复杂行为

• 批准号: 7388623
• 负责人: Noboru Hiroi
• 金额: $ 24.57万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388623
• 关键词: 22q11; 22q11.2; Adult; Affect; Attention deficit hyperactivity disorder; Attenuated; Behavior; Behavior Disorders; Behavioral; Behavioral Mechanisms; Biological Models; Boxing; Brain; Cardiovascular system; Cell division; Chromosomes, Human, Pair 16; Complex; Conflict (Psychology); Congenital Heart Defects; Data; Defect; DiGeorge Syndrome; Disease; Genes; Genetic; Goals; Hereditary Disease; Homologous Gene; Human; Hyperactive behavior; Individual; Knockout Mice; Light; Mental Depression; Motor Activity; Mus; Nature; Obsessive-Compulsive Disorder; Outcome; Phenotype; Predisposition; Principal Investigator; Proteins; Rate; Reporting; Rodent; Role; Schizophrenia; Shprintzen syndrome; Social Behavior; Social Interaction; Social isolation; Solid; Symptoms; System; Testing; Thymus Gland; Viral Vector; base; craniofacial; developmental disease; gene interaction; innovation; knockout gene; middle ear; mouse model; neuropsychiatry; novel; postnatal; prepulse inhibition; protein expression; research study; restoration; transcription factor

DESCRIPTION (provided by applicant): DiGeorge syndrome (DGS)/velo-cardio-facial syndrome (VCFS) is one of the common genetic disorders and affects approximately one in 4000 livebirths. Hemizygosity of a 1.5-3.0 Mb region of the human 22q11 underlies various neuropsychiatric, behavioral and physical abnormalities in DGS/VCFS. They include behavioral excitation, impaired prepulse inhibition, social interaction problems, as well as cardiovascular defects. Although efforts have been made in identifying individual 22q11 genes responsible for the behavioral abnormalities of DGS/VCFS, little is known about how individual 22q11 genes interact in increasing the susceptibility to these behavioral abnormalities. We and others have shown that deletion of either the T-box transcription factor Tbx1 or Cdcrel (cell division control related protein, also called Sept5) induces some, but not all DGS/VCFS symptoms in mice. To study the interactive role of Tbx1 and Cdcrel, the Principal Investigator has developed a double Tbx1/Cdcrel heterozygous mouse. Using this mouse line together with Tbx1 heterozygous mice and Cdcrel heterozygous/knockout mice, we have further shown that mice with combined heterozygosity of Tbx1 and Cdcrel, but not mice with deletion of either Tbx1 or Cdcrel alone, have sensitized hyperactivity. This suggests that Tbx1 and Cdcrel synergistically increase the susceptibility to the behavioral abnormalities of DGS/VCFS. Our long-term goal is to ascertain the nature of interaction among 22q11 genes as one of the underlying mechanisms for the behavioral abnormalities of DGS/VCFS. The specific hypothesis to be tested in this R21 proposal is that Tbx1 and Cdcrel interactively contribute to distinct behavioral abnormalities in mice. The specific aims to test this hypothesis are: Specific Aim 1: To determine whether heterozygosity of Tbx1, Cdcrel, or their combination causes abnormalities in locomotor activity/habituation, prepulse inhibition and social behaviors in mice (Experiments 1- 3). We will use Tbx1 heterozygous mice, Cdcrel heterozygous and knockout mice, double Tbx1/Cdcrel heterozygous mice, and their wild-type littermates. Specific Aim 2: To determine whether behavioral abnormalities seen in double heterozygous mice are attenuated by restoration of Cdcrel by a viral vector in the brain (Experiment 4). The present R21 proposal will provide a mouse model to further ascertain the nature of interaction between Tbx1 and Cdcrel in the brain in relation to behavioral abnormalities. The proposal will form a solid basis to further study the genetic basis of this common developmental disorder. Because deletion of 22q11 is also associated with high rates of schizophrenia, obsessive compulsive disorder, and attention deficit hyperactivity disorder, the outcome of this project will have significant implications for a better understanding of the genetic mechanisms of these neuropsychiatric disorders as well. The proposed project will ascertain the role of two 22q11 genes in behavioral abnormalities in a double heterozygous mouse model. Because hemizygosity of this chromosomal region is associated with many neuropsychiatric disorders and behavioral abnormalities, the outcome of the proposed studies will contribute to a better understanding of the genetic mechanisms underlying neuropsychiatric disorders, including schizophrenia.

描述（由申请人提供）：Digeorge综合征（DGS）/Velo-Cardio-Cardio-Facial综合征（VCF）是常见的遗传疾病之一，大约影响了4000个Live Bivebirth。人类22q11的1.5-3.0 MB区域的半合子是DGS/VCF中各种神经精神，行为和身体异常的基础。它们包括行为激发，预硫化抑制作用受损，社会相互作用问题以及心血管缺陷。尽管已经为确定负责DGS/VCF行为异常的单个22q11基因而做出了努力，但对于单个22q11基因如何相互作用，在增加对这些行为异常的敏感性方面如何相互作用。我们和其他人表明，T-box转录因子TBX1或CDCREL（细胞分裂对照相关蛋白，也称为SEPT5）的缺失会引起一些DGS/VCFS症状。为了研究TBX1和CDCREL的互动作用，主要研究者已经开发了双重TBX1/CDCREL杂合小鼠。使用该小鼠系与TBX1杂合小鼠和CDCREL杂合子/基因敲除小鼠一起，我们进一步表明，TBX1和CDCREL的杂合性的小鼠却不是单独缺失TBX1或CDCREL的小鼠，具有敏感性多动。这表明TBX1和CDCREL协同增强了对DGS/VCF行为异常的敏感性。我们的长期目标是确定22q11基因之间相互作用的性质，作为DGS/VCF行为异常的潜在机制之一。在此R21建议中要检验的特定假设是TBX1和CDCREL交互作用有助于小鼠的不同行为异常。检验该假设的具体目的是：具体目的1：确定TBX1，CDCREL或其组合的杂合性是否会导致运动/习惯性/习惯，小鼠的预硫化和社交行为的异常（实验1-3）。我们将使用TBX1杂合小鼠，CDCREL杂合子和基因敲除小鼠，双TBX1/CDCREL杂合小鼠及其野生型窝窝。具体目的2：确定在双重杂合小鼠中看到的行为异常是否通过大脑中病毒载体恢复CDCREL的衰减（实验4）。目前的R21提案将提供小鼠模型，以进一步确定大脑中TBX1和CDCREL之间相互作用的性质与行为异常有关。该提案将构成扎实的基础，以进一步研究这种常见发育障碍的遗传基础。由于22q11的缺失也与高精神分裂症，强迫症和注意力缺陷多动障碍率有关，因此该项目的结果将对更好地理解这些神经精神疾病的遗传机制具有重要意义。提出的项目将确定两个22q11基因在双重杂合小鼠模型中行为异常中的作用。由于该染色体区域的半齐与许多神经精神疾病和行为异常有关，因此所提出的研究的结果将有助于更好地理解包括精神分裂症在内的神经精神疾病的遗传机制。