Role of Sema7A in functional organization of neocortex

描述（由申请人提供）：认知、社交和感知功能障碍与皮质突触回路发育和可塑性异常相关。这类疾病有很强的遗传倾向，但确切的原因尚不清楚。染色体15 q24的微缺失与自闭症综合征有关。最近一项关于15 q24微缺失综合征的研究发现了一个最小的缺失区间，该区间仅包含四个在大脑中表达的基因，其中SEMA 7A与该综合征相关的感觉功能障碍高度相关。Sema 7A是脑信号蛋白家族的一个非典型成员：它通过GPI连接锚定在膜上;它主要在出生后的神经系统中表达;并且它可以以1整合素依赖的方式促进轴突延伸。这些发现指出，Sema 7A在大脑发育的后期阶段具有不同于在胚胎发育期间产生轴突排斥的常规Semaphorin-Plexin相互作用的作用，但这尚未被探索。我们的数据表明，Sema 7A在突触发育和感觉经验驱动连接细化的时候，在体感（S1）皮层中特别丰富。因此，我们推测，Sema 7A功能的成熟和微调皮质微电路发生在出生后早期的发展。在小鼠S1桶皮质我们的初步数据表明，当Sema 7A基因消融丘脑皮质轴突达到第IV层，但他们的突触未能成熟的功能和他们的突触后树突状细胞的目标文件，以适当地定向他们的乔木。相比之下，皮层下中枢的躯体感觉地图是正常的。这些数据概述了一个全新的分子贡献皮层感觉地图的功能和结构的发展，没有它可能会扰乱信息处理通过皮层微电路，反过来，产生相关的症状15 q24微缺失综合征。我们的初步数据作为假设的基础，Sema 7A是必不可少的正常S1成熟和功能。 公共卫生相关性：拟议的研究将定义在15 q24微缺失综合征中缺失的非典型脑信号蛋白的新生物学作用，该综合征与自闭症谱系障碍（ASD）具有共同特征;推进对皮质感觉地图组织和发育的分子控制的理解;并揭示了新的见解，在皮层电路的发展变化，可能是认知和知觉障碍与ASD相关的基础，相关的病理。

DESCRIPTION (provided by applicant): Disorders of cognitive, social and perceptual functions are associated with abnormalities of cortical synaptic circuit development and plasticity. There is a strong genetic disposition to such diseases, but the precise causes are unknown. Microdeletions in chromosome 15q24 are associated with a syndrome that features autism. A recent study of 15q24 microdeletion syndrome identified a minimal deletion interval that contains only four genes that are expressed in brain, among which, SEMA7A stands apart as highly relevant to sensory dysfunctions associated with the syndrome. Sema7A is an atypical member of the Semaphorin family of guidance cues: it is membrane-anchored by a GPI-linkage; it is expressed principally postnatally in the nervous system; and it can promote axon extension in a ¿1 integrin-dependent manner. These findings point to the idea that Sema7A has roles in late stages of brain development distinct from the customary Semaphorin-Plexin interactions that generate axon repulsion during embryonic development, but this has not been explored. Our data show that Sema7A is particularly enriched in somatosensory (S1) cortex at a time when synapses develop and sensory experience drives the refinement of connectivity. Accordingly, we hypothesize that Sema7A functions in the maturation and fine-tuning of cortical microcircuitry that occurs during early postnatal development. In mouse S1 barrel cortex our preliminary data show that when Sema7A is genetically ablated thalamocortical axons reach layer IV, but their synapses fail to mature functionally and their postsynaptic dendritic targets fil to orient their arbors appropriately. In contrast, somatosensory maps in subcortical centers are normal. These data outline an entirely novel molecular contribution to the functional and structural development of cortical sensory maps, the absence of which may perturb information processing through cortical microcircuits that in turn, produce symptoms relevant to 15q24 microdeletion syndrome. Our preliminary data serve as the basis for the hypothesis that Sema7A is essential for normal S1 maturation and function. PUBLIC HEALTH RELEVANCE: The proposed studies will define novel biological roles of an atypical Semaphorin that is deleted in 15q24 Microdeletion Syndrome, a syndrome that shares features with Autism Spectrum Disorders (ASD); advance understanding of the molecular control of cortical sensory map organization and development; and reveal new insights into developmental alterations in cortical circuitry that may underlie cognitive and perceptual impairments associated with ASD-related pathologies.