Regulation of 22q11 Genes in Embroyonic and Adult Forebrain

描述（由申请人提供）：22 q11缺失综合征（22 q11 DS，也称为DiGeorge或Velocardiofacial综合征）发生在大约1/3000的活产婴儿中，并使语言和社会认知缺陷、注意力缺陷/多动症、自闭症、情绪障碍和精神分裂症的脆弱性增加。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然不明确。皮质电路的行为障碍与特定的遗传病变（在hChr.22，q11位置缺失1.5至3.0MB）的关联为评估导致发病的细胞和分子机制提供了机会。在该项目的第一阶段，我们发现在22 q11 DS中缺失的大量基因在发育和成人神经系统的不同区域和细胞类别中的特定时间表达。我们对小鼠22 q11直系同源物的功能分析将这些基因分为3类：1.受信号分子调节的基因，影响22 q11 DS表型位点（包括心脏、面部、胸腺、四肢和前脑）的诱导和形态发生。2.）的情况。与细胞周期调控有关的基因。3.）第三章定位于线粒体的影响细胞代谢的基因。表达动态和模式，以及明显的功能，每个基因子集，提出了一个新的假设，22 q11缺失如何改变皮层电路的发展：改变剂量的功能不同的22 q11基因子集破坏规格，增殖，迁移，生长和电路分化的皮层神经元或其前体。为了验证这个假设，我们将追求三个具体目标。1.）我们将评估减少22 q11基因剂量和诱导信号之间的相互作用，影响皮质区域的身份和神经能力。我们专注于22 q11基因，音刺猬，视黄酸和骨形态发生信号通路的相互调节。2.）我们将定义减少22 q11基因剂量皮质神经发生和迁移的后果。我们评估潜在的调制前体细胞增殖的22 q11细胞周期调控基因表达最大的皮质神经发生在脑室/脑室下区。3.）第三章我们将确定是否皮质投射神经元突触的形成和过程的增长受到22 q11基因剂量减少。我们评估22 q11基因在皮质突触发生过程中最大程度表达的作用，其定位和功能暗示它们参与线粒体代谢调控。我们的研究结果将确定是否减少22 q11基因剂量妥协规范，起源和突触形成皮层投射神经元。因此，我们将提供一个大纲的细胞和分子机制，可以有助于皮质发病机制的范围内的行为障碍与22 q11 DS。 公共卫生相关性：对于基因突变和毁灭性行为障碍之间的关系，包括自闭症、精神发育迟滞、注意力缺陷/多动障碍（ADHD）、情绪障碍和精神分裂症，仍然知之甚少。该项目的重点是消除22号染色体上少量基因的两个拷贝中的一个的突变，导致称为DiGeorge，Velo-cardio-facial或22 q11缺失综合征的疾病，其中患者患这些神经和精神疾病的风险高度增加。同样的突变可以在小鼠中建模，人们可以确定这种相对较小（32-50）的基因组的降低水平如何破坏大脑发育或功能。因此，我们的研究有助于解释特定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，精神发育迟滞，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.