22q11 Genes and Complex Behavior in Mice

描述（由申请人提供）：DiGeorge综合征（DGS）/腭心面综合征（VCFS）是常见的遗传性疾病之一，大约每4000例活产中就有1例受影响。人类22 q11的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、前脉冲抑制受损、社会交往问题以及心血管缺陷。虽然已经努力确定个别22 q11基因负责DGS/VCFS的行为异常，很少有人知道个别22 q11基因如何相互作用，增加这些行为异常的易感性。我们和其他人已经表明，T-box转录因子Tbx 1或Cdcrel（细胞分裂控制相关蛋白，也称为Sept 5）的缺失会诱导小鼠的一些但不是所有DGS/VCFS症状。为了研究Tbx 1和Cdcrel的相互作用，主要研究者开发了双Tbx 1/Cdcrel杂合子小鼠。将该小鼠系与Tbx 1杂合小鼠和Cdcrel杂合/敲除小鼠一起使用，我们进一步表明，具有Tbx 1和Cdcrel的组合杂合性的小鼠，而不是具有单独的Tbx 1或Cdcrel缺失的小鼠，具有致敏性多动症。这表明Tbx 1和Cdcrel协同增加对DGS/VCFS行为异常的易感性。我们的长期目标是确定22 q11基因之间的相互作用的性质作为DGS/VCFS行为异常的潜在机制之一。在这个R21提案中要测试的特定假设是Tbx 1和Cdcrel交互地导致小鼠中的不同行为异常。具体目的1：确定Tbx 1、Cdcre 1或其组合的杂合性是否导致小鼠的运动活动/习惯化、前脉冲抑制和社会行为异常（实验1- 3）。我们将使用Tbx 1杂合小鼠、Cdcrel杂合和敲除小鼠、双Tbx 1/Cdcrel杂合小鼠及其野生型同窝仔。具体目标二：为了确定在双杂合小鼠中观察到的行为异常是否通过脑中的病毒载体恢复Cdcrel而减弱（实验4）。目前的R21提案将提供小鼠模型，以进一步确定Tbx 1和Cdcrel在大脑中与行为异常相关的相互作用的性质。该提案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22 q11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病率相关，因此该项目的结果也将对更好地理解这些神经精神疾病的遗传机制产生重大影响。该项目将确定两个22 q11基因在双杂合小鼠模型中行为异常的作用。由于该染色体区域的半合子与许多神经精神疾病和行为异常相关，因此拟议研究的结果将有助于更好地了解神经精神疾病（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.