Role of Sema7A in functional organization of neocortex

描述(申请人提供)：认知、社交和知觉功能障碍与皮质突触回路发育和可塑性异常有关。这些疾病有很强的遗传倾向，但确切的原因尚不清楚。染色体15q24上的微缺失与一种以自闭症为特征的综合征有关。最近对15q24微缺失综合征的研究发现了一个最小的缺失间隔，它只包含四个在大脑中表达的基因，其中SEMA7A与该综合征相关的感觉功能障碍高度相关。Sema7A是Semaphorin引导线索家族中的一个非典型成员：它是由GPI连接的膜锚定的；它主要在出生后的神经系统中表达；它可以以整合素依赖的方式促进轴突延伸。这些发现表明，Sema7A在大脑发育的后期阶段具有不同于通常的Semaphorin-Plexin相互作用的观点，后者在胚胎发育期间产生轴突排斥，但这一点尚未被探索。我们的数据显示，在突触发育和感觉体验推动连接精细化的时候，Sema7A在躯体感觉(S1)皮质中特别丰富。因此，我们假设Sema7A在出生后早期发育过程中皮质微回路的成熟和微调中发挥作用。在小鼠S1桶皮质，我们的初步数据显示，当Sema7A被基因消融时，丘脑皮质轴突达到IV层，但它们的突触未能在功能上成熟，它们的突触后树突靶点填满，以适当地定向它们的乔木。相比之下，皮质下中心的体感地形图是正常的。这些数据概述了一种全新的分子对皮质感觉图功能和结构发展的贡献，缺乏该图可能会扰乱通过皮质微电路进行的信息处理，从而产生与15q24微缺失综合征相关的症状。我们的初步数据为Sema7A是正常S1成熟和功能所必需的假设提供了基础。

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.