Characterizing human-specific expression of ZP2 in the cerebellum

摘要 寻找治疗神经精神障碍的新疗法是当务之急，因为这些障碍影响超过 每五个美国成年人中就有一个，每年花费美国医疗保健系统超过1800亿美元。挑战 限制对新疗法的追求包括1)与使用动物建立更高模型相关的问题 认知行为和2)不同大脑区域的含义，当被破坏时，表现在 运动、情感和认知领域的不同症状。为了解决这些问题，这项提案 将表征ZP2基因的表达和缺失相关表型，该基因表现出 在小脑中有人类特有的表达。小脑最近被牵连到 协调更高的认知功能，它的中断不仅与运动有关，而且 也有认知和情感症状。在一项对大脑的全面转录研究中， 在研究人类和灵长类动物之间的差异基因表达时，塞斯坦实验室发现 ZP2，一种典型的参与稳定细胞外基质和防止多精受精的蛋白质 哺乳动物的卵母细胞，也是人类小脑中唯一表达的。这项提案将调查 ZP2在颗粒细胞树突上的潜在类似作用，假设ZP2锚定在那里 并指导苔藓纤维在突触发生和发育过程中的相互作用。要做到这一点，这个提议 包括利用出生后、手术后和死后人脑组织以及分化的人类 以诱导多能干细胞为模型系统定位ZP2表达，确定ZP2结合 伙伴，并确定ZP2是否在突触的发育中有机械上的牵连 在小脑颗粒细胞和苔藓纤维之间。这项工作有可能阐明 突触发育机制可能是人类独有的，也是潜在的分子靶点 定位于小脑的人类特有的认知功能。此应用程序还包括一个 培训计划将使申请者为研究神经发育障碍的职业做好准备 一位临床医生兼科学家。

SUMMARY Finding new treatments for neuropsychiatric disorders is a priority, as these disorders affect over 1 in 5 US adults and cost the US health care system over 180 billion dollars annually. Challenges limiting the pursuit of new treatments include 1) issues associated with using animals to model higher cognitive behaviors and 2) the implication of disparate brain regions that, when disrupted, manifest in diverse symptoms in motor, affective, and cognitive domains. To address these issues, this proposal will characterize the expression and deletion-associated phenotypes of a gene, ZP2, that exhibits human-specific expression in the cerebellum. The cerebellum has recently been implicated in coordinating higher cognitive functions, and its disruption has been associated not only with motor but also with cognitive and affective symptoms. In a comprehensive transcriptomic study of the brain, examining differential gene expression between humans and primates, the Sestan lab discovered that ZP2, a protein canonically involved in stabilizing the extracellular matrix and preventing polyspermy at the mammalian oocyte, is also uniquely expressed in human cerebellum. This proposal will investigate a potential analogous role of ZP2 at the granule cell dendrite, where it is hypothesized that ZP2 anchors and guides mossy fiber interactions during synaptogenesis and development. To do so, this proposal includes utilizing postnatal post-surgical and post-mortem human brain tissue and differentiated human induced pluripotent stem cells as a model system to localize ZP2 expression, determine ZP2 binding partners, and determine whether ZP2 is mechanistically implicated in the development of synapses between cerebellar granule cells and mossy fibers. This work has the potential to shed light on mechanisms of synaptic development that may be unique to humans and a potential molecular target for human-specific cognitive functioning localized to the cerebellum. This application also includes a training plan that will prepare the applicant for a career investigating neurodevelopmental disorders as a clinician-scientist.