Role of Sema7A in functional organization of neocortex

Sema7A 在新皮质功能组织中的作用

• 批准号: 8514077
• 负责人: Deanna L Benson
• 金额: $ 36.61万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-19 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514077
• 关键词: 15q24; Ablation; Acute; Animals; Area; Autistic Disorder; Axon; Binding; Biochemical; Biological; Biological Models; Brain; Brain Stem; Cells; Chromosomes; Cognition Disorders; Cognitive; Cues; Data; Defect; Dendrites; Development; Disease; Electroporation; Embryonic Development; Environment; Family; Functional disorder; Genes; Genetic; Image; Impaired cognition; Impairment; Integrins; Maps; Mediating; Membrane; Methods; Molecular; Mus; Neocortex; Nervous system structure; Neurons; Olfactory Pathways; Pathology; Pathway interactions; Photons; Positioning Attribute; Property; Relative (related person); Role; Semaphorins; Sensory; Signal Transduction; Slice; Staging; Symptoms; Synapses; Syndrome; Testing; Thalamic structure; Time; Tissues; Trigeminal System; Vibrissae; Whole-Cell Recordings; autism spectrum disorder; barrel cortex; base; critical period; experience; gain of function; in utero; in vivo; in vivo Model; information processing; insight; member; microdeletion; multidisciplinary; mutant; nervous system development; neural circuit; novel; plexin; postnatal; postsynaptic; presynaptic; receptor; research study; social; somatosensory

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.

描述（申请人提供）：认知、社会和知觉功能障碍与皮层突触回路发育和可塑性异常有关。这类疾病有很强的遗传倾向，但确切的原因尚不清楚。15q24染色体的微缺失与一种以自闭症为特征的综合症有关。最近一项关于15q24微缺失综合征的研究发现了一个极小的缺失间隔，该缺失间隔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是信号蛋白家族的一个非典型成员：它是由gpi连锁膜锚定的；它主要在出生后的神经系统中表达；它能以1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发挥作用，而不是在胚胎发育期间产生轴突排斥的惯常信号素-丛蛋白相互作用，但这一点尚未得到探讨。我们的数据表明，Sema7A在突触发育和感官体验驱动连接完善的时候，在体感（S1）皮层中特别丰富。因此，我们假设Sema7A在出生后早期发育过程中皮层微回路的成熟和微调中起作用。在小鼠S1桶皮质中，我们的初步数据显示，Sema7A基因切除后，丘脑皮质轴突到达第4层，但它们的突触在功能上未能成熟，突触后树突靶点会适当地定向它们的树突。相反，皮层下中心的体感图是正常的。这些数据概述了一种全新的分子对皮质感觉图谱功能和结构发育的贡献，这种图谱的缺失可能会干扰皮质微回路的信息处理，进而产生与15q24微缺失综合征相关的症状。我们的初步数据为Sema7A对正常S1成熟和功能至关重要的假设提供了基础。