Regulation of 22q11 Genes in Embryonic & Adult Forebrain

描述（由申请人提供）：22q11染色体微缺失综合征（22q11DS）是已知的最常见的存活缺失综合征。除了心脏、面部和肢体畸形外，22q11DS还被定义为行为异常和对包括精神分裂症在内的几种精神疾病的易感性增加。显然，22q11单倍不足会改变大脑的发育或功能，尤其是在行为和精神疾病中受损的前脑区域和回路。然而，单倍不全对22q11基因在前脑中的表达或活性的影响尚不清楚。我们的初步证据表明，从早期发育到成年，29个22q11同源基因中有18个在整个前脑表达。因此，我们将评估在广泛分布于所有前脑细分的特定细胞类别中存在多个22q11基因协同表达的假设。如果是这样的话，22q11的多基因单倍不足，而不是任何单一基因的功能不足，可能会为改变前脑特定细胞类别或回路的发育建立一个阈值。前脑、心脏、四肢和面部的间充质/上皮诱导的改变可能会进一步放大这一主要作用。此外，22q11同源物的持续表达，可能在特定的分化细胞类别中，表明单倍体不足可能进一步损害成熟前脑细胞和电路元件的功能或维持。为了验证我们的假设，我们将确定22q11同系物的一个子集的细胞类别特异性。我们选择这些基因是基于它们在发育和成年前脑中显著和持续的表达水平、基因组组织、推断的神经功能以及与行为或精神疾病的关联。此外，我们将分析间充质/上皮相互作用在调节22q11基因表达中的作用。最后，我们将评估22q11单倍不足对发育中和成年前脑的表达模式、水平和细胞表型的影响。因此，我们的实验将建立22q11DS中行为和精神表型的细胞底物，并深入了解22q11单倍性不足损害前脑结构和功能的发育和基因组机制。

DESCRIPTION (provided by applicant): The 22q11 Chromosomal Microdeletion Syndrome (22q11DS) is the most common survivable deletion syndrome known. In addition to heart, face and limb malformations, 22q11DS is defined by behavioral anomalies and increased susceptibility to several psychiatric diseases including schizophrenia. Apparently, 22q11 haploinsufficiency alters brain development or function, particularly forebrain regions and circuits compromised in behavioral and psychiatric disorders. Nevertheless, the effects of haploinsufficiency on expression or activity of 22q11 genes in the forebrain remain unknown. Our preliminary evidence suggests that 18 of 29 routine 22q11 homologues are expressed throughout the forebrain from early development through adulthood. Accordingly, we will evaluate the hypothesis that there is concerted expression of multiple 22q11 genes in specific cell classes distributed broadly in all forebrain subdivisions. If this is the case, multigenic haploinsufficiency at 22q11, rather than the function of any single gene, might establish a threshold for altered development of specific cell classes or circuits throughout the forebrain. This primary effect may be further amplified by alterations in mesenchymal/epithelial induction that mediates initial differentiation in the forebrain as well as the heart, limbs and face. Moreover, continued expression of 22q11 homologues, perhaps in specific differentiated cell classes, suggests that haploinsufficiency might further compromise function or maintenance of mature forebrain cells and circuit elements. To test our hypothesis we will determine cell-class specificity of a subset of the 22q11 homologues. We selected these genes based upon their significant and sustained expression levels in the developing and adult forebrain, genomic organization, inferred neural function and association with behavioral or psychiatric disorders. In addition, we will analyze the role of mesenchymal/epithelial interactions in modulating 22q11 gene expression. Finally, we will evaluate the consequences of 22q11 haploinsufficiency for expression patterns, levels and cellular phenotype in the developing and adult forebraIn. Thus, our experiments will establish the cellular substrates for the behavioral and psychiatric phenotypes seen in 22q11DS, and give insight into the developmental and genomic mechanisms by which haploinsufficiency at 22q11 compromises forebrain structure and function.