22q11 Genes and Complex Behavior in Mice

描述(申请人提供)：DiGeorge综合征(DGS)/心脏面部畸形综合征(VCFS)是一种常见的遗传性疾病，大约每4000名活产儿中就有一人受到影响。人类22q11的1.5-3.0Mb区域的半杂合性是DGS/VCFS各种神经精神、行为和生理异常的基础。它们包括行为兴奋、受损的脉搏前抑制、社交问题以及心血管缺陷。虽然已经努力确定导致DGS/VCFs行为异常的单个22q11基因，但关于单个22q11基因如何相互作用增加这些行为异常的易感性还知之甚少。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一些但不是全部的DGS/VCFS症状。为了研究tbx1和cdcrel的相互作用，首席研究员开发了一种双tbx1/cdcrel杂合子小鼠。将该小鼠系与TBX1杂合子小鼠和CDCrel杂合子/基因敲除小鼠一起使用，我们进一步表明，TBX1和CDcrel杂合子结合的小鼠，而不是TBX1或CDcrel单独缺失的小鼠，具有敏感性多动。这表明，Tbx1和CDcrel协同作用增加了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。在这个R21提案中要测试的特定假设是，TBX1和CDcrel交互作用导致小鼠明显的行为异常。检验这一假说的具体目的是：具体目标1：确定tbx1、cdcrel或其组合的杂合性是否会导致小鼠的运动活动/习惯性、脉搏前抑制和社会行为的异常(实验1-3)。我们将使用TBX1杂合子小鼠、CDCREL杂合子和基因敲除小鼠、双TBX1/CDCREL杂合子小鼠及其野生型窝种。具体目标2：确定双杂合小鼠的行为异常是否可以通过大脑中的病毒载体恢复CDcrel来减轻(实验4)。目前的R21方案将提供一个小鼠模型，以进一步确定与行为异常有关的脑内TBX1和CDcrel之间相互作用的性质。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基因缺失还与精神分裂症、强迫症和注意缺陷多动障碍的高发病率相关，因此该项目的结果将对更好地理解这些神经精神障碍的遗传机制具有重要意义。这项拟议的项目将确定两个22q11基因在双杂合小鼠模型行为异常中的作用。由于该染色体区域的半杂合性与许多神经精神障碍和行为异常有关，拟议的研究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障碍的遗传机制。

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.