A human neurodevelopmental model for Williams syndrome

 描述（由申请人提供）：本提案的主要目标是确定特定基因对威廉综合征（WS）相关细胞和分子表型的贡献。WS是一种遗传性神经发育障碍，其特征是异常的过度社交和保留和受损的语言和认知能力的马赛克。WS是由染色体带7q11.23中约25个基因的半合子缺失引起的。这种疾病的治疗完全是对症的：没有治愈性或疾病修饰疗法。我们使用细胞重编程技术从WS和通常发育（TD）个体产生诱导多能干细胞（iPSC）。我们的数据显示，WS神经祖细胞（NPC）的凋亡增加和WS皮质层V/VI神经元的神经元树突的更高的复杂性。我们还对活体受试者的大脑进行了结构成像，发现与TD相比，WS显示出皮质表面积减少。此外，我们进行了形态计量学分析的皮质神经元从死后的人脑，类似的iPSC衍生的神经元，我们还发现更长的总树突和增加的数量在WS的棘。因此，我们假设，删除某些基因在WS区域可以导致太具体的缺陷，在人类NPC和神经元。为了将基因与细胞和分子表型联系起来，我们提出了以下具体目标：目标1：确定WS和目标2中FZD 9和GTF 2 I缺失细胞和分子表型的影响：测量WS和TD死后成人和发育中脑组织中的皮质神经元形态和密度。这些实验将使我们能够确定FZD 9和GTF 2 I缺失对WS细胞和分子表型的影响。我们的发现将把这两个基因与可能导致WS社会行为的特定细胞缺陷联系起来。体外细胞表型的直接比较将来自死后脑组织定量。这些信息不仅对WS很重要，而且对影响人类社会大脑的其他人类发育状况也很重要，例如自闭症谱系障碍。

 DESCRIPTION (provided by applicant): The main goal of this proposal is to define the contribution of specific genes to cellular and molecular phenotypes relevant to William's syndrome (WS). WS is a genetic neurodevelopmental disorder characterized by an unusual hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. WS is caused by a hemizygous deletion of approximately 25 genes in chromosome band 7q11.23. Treatment for this disorder is entirely symptomatic: there are no curative or disease modifying therapies. We used cellular reprogramming technologies to generate induced pluripotent stem cells (iPSCs) from WS and typically developing (TD) individuals. Our data revealed increased apoptosis in WS neural progenitor cells (NPCs) and a higher complexity of neuronal dendrites in WS cortical layer V/VI neurons. We also used structural imaging of the brains of living subjects and found that WS showed decreased cortical surface area compared to TD. Additionally, we performed a morphometric analysis of cortical neurons from postmortem human brains and, similar to the iPSC-derived neurons, we also revealed longer total dendrites and increased number of spines in WS. Thus, we hypothesize that deletion of certain genes in the WS region can lead too specific defects in human NPCs and neurons. To link genes to cellular and molecular phenotypes, we propose the following specific aims: Aim 1: Determine the impact of the FZD9 and GTF2I deletion cellular and molecular phenotypes in WS and Aim 2: Measure cortical neuronal morphology and density in WS and TD postmortem adult and developing brain tissue. These experiments will allow us to determine the impact of the FZD9 and GTF2I deletions on the WS cellular and molecular phenotypes. Our findings will connect these two genes to specific cellular defects that may contribute to WS social behaviors. Direct comparison of cellular phenotypes in vitro will come from postmortem brain tissue quantification. This information will be important not only for WS, but also for other developmental human conditions affecting the human social brain, such as autism spectrum disorders.