22q11 Genes and Complex Behavior in Mice

描述（由申请人提供）：diggeorge综合征(DGS)/velo-cardio-facial syndrome （VCFS）是一种常见的遗传性疾病，大约每4000个活产婴儿中就有一个受到影响。人类22q11 1.5-3.0 Mb区域的半合子性是DGS/VCFS中各种神经精神、行为和身体异常的基础。它们包括行为兴奋，脉冲前抑制受损，社会互动问题，以及心血管缺陷。尽管已经努力确定导致DGS/VCFS行为异常的个体22q11基因，但对于个体22q11基因如何相互作用增加对这些行为异常的易感性知之甚少。我们和其他人已经证明，T-box转录因子Tbx1或Cdcrel（细胞分裂控制相关蛋白，也称为Sept5）的缺失会在小鼠中引起部分（但不是全部）DGS/VCFS症状。为了研究Tbx1和Cdcrel的相互作用，首席研究员开发了双Tbx1/Cdcrel杂合小鼠。将该小鼠系与Tbx1杂合小鼠和Cdcrel杂合/敲除小鼠一起使用，我们进一步表明，Tbx1和Cdcrel混合杂合的小鼠，而不是单独缺失Tbx1或Cdcrel的小鼠，具有致敏性亢进。这表明Tbx1和Cdcrel协同增加了DGS/VCFS行为异常的易感性。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/VCFS行为异常的潜在机制之一。在R21提案中需要验证的具体假设是Tbx1和Cdcrel相互作用导致小鼠明显的行为异常。验证这一假设的具体目的是：具体目的1：确定Tbx1、Cdcrel的杂合性或它们的组合是否会导致小鼠运动活动/习惯化、脉冲前抑制和社会行为的异常（实验1- 3）。我们将使用Tbx1杂合小鼠，Cdcrel杂合和敲除小鼠，双Tbx1/Cdcrel杂合小鼠及其野生型仔鼠。特异性目的2：确定双杂合小鼠的行为异常是否可以通过脑内病毒载体恢复Cdcrel而减轻（实验4）。目前的R21提案将提供一个小鼠模型，以进一步确定Tbx1和Cdcrel在大脑中与行为异常相关的相互作用的性质。该建议将为进一步研究这种常见发育障碍的遗传基础奠定坚实的基础。由于22q11的缺失也与精神分裂症、强迫症和注意缺陷多动障碍的高发率有关，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。该项目将在双杂合小鼠模型中确定两个22q11基因在行为异常中的作用。由于该染色体区域的半合子性与许多神经精神疾病和行为异常有关，因此拟议研究的结果将有助于更好地理解神经精神疾病（包括精神分裂症）的遗传机制。

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.