Regulation of 22q11 Genes in Embroyonic and Adult Forebrain

描述(申请人提供)：22q11Deletion综合征(22q11DS，也称为DiGeorge或VelHearofacesis)发生在大约1/3000的活产儿中，并增加了语言和社会认知缺陷、注意力缺陷/多动障碍、自闭症、情绪障碍和精神分裂症的易感性。人们普遍认为，这些疾病反映了皮质神经元和回路的发育或维持受损；然而，细胞和分子致病机制仍不清楚。皮质回路的行为障碍与特定的遗传损伤--hChr.22基因缺失1.5-3.0MB，位置Q11--的关联为评估致病的细胞和分子机制提供了机会。在这个项目的第一阶段，我们发现在22q11DS中缺失的大量基因在发育中的神经系统和成人神经系统中的不同区域和细胞类别的特定时间表达。我们对小鼠22q11同源基因的功能分析将这些基因分为3类：1)受信号分子调控的基因影响22q11DS表型位点的诱导和形态发生，包括心脏、面部、胸腺、四肢和前脑。2.)与细胞周期调控有关的基因。3.)基因定位于线粒体，影响细胞新陈代谢。表达动态和模式，以及每个基因亚群的明显功能，为22q11缺失如何改变皮质回路发育提出了一个新的假说：改变剂量的功能不同的22q11基因亚群扰乱了皮质神经元或其前体的规范、增殖、迁移、生长和回路分化。为了验证这一假设，我们将追求3个具体目标。1)我们将评估减少的22q11基因剂量和影响皮质区域识别和神经发生能力的诱导信号之间的相互作用。我们着重于22q11基因、声波刺猬、维甲酸和骨形态发生信号通路的相互调节。2.)我们将确定22q11基因剂量减少对皮质神经发生和迁移的影响。我们评估了22q11细胞周期调控基因在脑室/室下区皮质神经发生过程中表达最多的对前体细胞增殖的潜在调节作用。3.)我们将确定皮质投射神经元突触的形成和突起生长是否会因22q11基因剂量的减少而受到影响。我们评估了22q11基因在皮质突触发生过程中最高表达的作用，以及它们的定位和功能与线粒体代谢调节的关系。我们的结果将确定22q11基因剂量减少是否影响皮质投射神经元的规格、发生和突触形成。因此，我们将提供在与22q11DS相关的行为障碍范围内有助于皮质发病的细胞和分子机制的概述。公共卫生相关性：目前对基因突变与破坏性行为障碍之间的关系仍知之甚少，这些行为障碍包括自闭症、智力低下、注意力缺陷/多动障碍(ADHD)、情绪障碍和精神分裂症。该项目专注于一种突变，它消除了22号染色体上少量基因的两个副本中的一个，导致了一种被称为DiGeorge、Velo心脏面部或22q11缺失综合征的疾病，在这种疾病中，患者患这些神经和精神疾病的风险极高。同样的突变可以在小鼠身上模拟，人们可以确定这种相对较小的(32-50)组基因水平降低是如何扰乱大脑发育或功能的。因此，我们的研究有助于解释特定的突变如何导致大脑发育和功能的变化，这些变化可能是自闭症、智力低下、多动症、情绪障碍和精神分裂症的基础。

DESCRIPTION (provided by applicant): 22q11Deletion Syndrome (22q11DS, also known as DiGeorge or Velocardiofacial Syndrome) occurs in approximately 1/3000 live births and confers increased vulnerability for language and social cognition deficits, attention deficit/hyperactivity disorder, autism, mood disorders, and schizophrenia. There is general consensus that these disorders reflect compromised development or maintenance of cortical neurons and circuits; nevertheless, cellular and molecular pathogenic mechanisms remain ill defined. The association of behavioral disorders of cortical circuitry with a specific genetic lesion-deletion of 1.5 to 3.0MB at hChr.22, position q11-provides an opportunity to evaluate cellular and molecular mechanisms that contribute to pathogenesis. In the first phase of this project we found that a large set of genes deleted in 22q11DS are expressed at specific times in distinct regions and cell classes in the developing and adult nervous system. Our functional analysis of mouse 22q11 orthologues divides these genes into 3 categories: 1.) Genes regulated by signaling molecules that influence induction and morphogenesis at 22q11DS phenotypic sites including the heart, face, thymus, limbs, and forebrain. 2.) Genes implicated in cell cycle regulation. 3.) Genes localized to mitochondria that influence cellular metabolism. The expression dynamics and patterns, as well as apparent functions of each gene subset, suggests a new hypothesis of how 22q11 deletion alters cortical circuit development: altered dosage of functionally distinct 22q11 gene subsets disrupts specification, proliferation, migration, growth and circuit differentiation of cortical neurons or their precursors. To test this hypothesis, we will pursue 3 Specific Aims. 1.) We will assess interaction between diminished 22q11 gene dosage and inductive signaling that influences cortical regional identity and neurogenic capacity. We focus on reciprocal regulation of 22q11 genes, sonic hedgehog, retinoic acid, and bone morphogenetic signaling pathways. 2.) We will define consequences of diminished 22q11 gene dosage for cortical neurogenesis and migration. We assess potential modulation of precursor proliferation by 22q11 cell cycle regulatory genes expressed maximally during cortical neurogenesis in the ventricular/subventricular zone. 3.) We will determine whether cortical projection neuron synapse formation and process growth is compromised by diminished 22q11 gene dosage. We evaluate roles of 22q11 genes expressed maximally during cortical synaptogenesis, and whose localization and function implicates them in mitochondrial regulation of metabolism. Our results will establish whether diminished 22q11 gene dosage compromises specification, genesis, and synapse formation for cortical projection neurons. Thus, we will provide an outline of cellular and molecular mechanisms that can contribute to cortical pathogenesis in the range of behavioral disorders associated with 22q11DS. PUBLIC HEALTH RELEVANCE: There is still little understanding of the relationship between genetic mutations and devastating behavioral disorders including autism, mental retardation, attention deficit/hyperactivity disorder (ADHD), mood disorders, and schizophrenia. This project focuses on a mutation that eliminates one out of two copies of a small number of genes on chromosome 22 resulting in a disorder known as DiGeorge, Velo-cardio-facial, or 22q11 Deletion Syndrome in which patients are at highly increased risk for these neurological and psychiatric diseases. The same mutation can be modeled in mice, and one can identify how reduced levels of this relatively small (32-50) set of genes disrupt brain development or function. Thus, our studies help explain how a specific mutation can lead to changes in brain development and function that may underlie autism, mental retardation, ADHD, mood disorders and schizophrenia.