Role of autism-linked genes in developmental refinement of the corpus callosum

自闭症相关基因在胼胝体发育细化中的作用

• 批准号: 9917831
• 负责人: Masaaki Torii
• 金额: $ 43.75万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917831
• 关键词: Affect; Anatomy; Axon; Biological; Biological Assay; Birth; CASP6 gene; Caspase; Cell Death; Cells; Cellular Structures; Cleaved cell; Clinical; Cognitive; Communication; Corpus Callosum; Critical Pathways; Data; Development; Diagnostic; Disease; Electron Microscopy; Electroporation; Genes; Genetic; Goals; Immunohistochemistry; Individual; Investigation; Label; Language Development; Life; Light; Link; MAPK8 gene; Maintenance; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Molecular; Molecular Target; Morphology; Motor; Mus; Neurodevelopmental Disorder; Neuroglia; Neurologic; Neurons; Organism; Pathogenesis; Pathway interactions; Pattern; Pharmacology; Phase; Phenotype; Physiological; Play; Process; Protein Kinase; Proteins; Proteomics; Regulation; Reporting; Role; Sensory; Signal Transduction; Signaling Protein; Structure; Study models; System; Techniques; Testing; Therapeutic; Time; Tubulin; autism spectrum disorder; autistic children; axon guidance; axonal degeneration; base; cognitive disability; experience; genome wide screen; in utero; insight; knock-down; link protein; malformation; mouse development; mouse model; myelination; novel; novel therapeutic intervention; plexin; postnatal; preservation; screening; single-cell RNA sequencing; spatiotemporal; supernova; synaptogenesis

The corpus callosum (CC) provides interhemispheric communication essential for cognitive and associative processes, with critical roles in several higher order functions including sensory processing, motor coordination, and language acquisition and formation. Malformation of the CC has devastating functional consequences; agenesis and hypoplasia of the CC is linked to several conditions associated with severe neurological and cognitive disabilities. In addition, anatomical and physiological deficits of the CC also have been commonly reported in several neurodevelopmental disorders such as Autism Spectrum Disorders (ASD). Yet, the cellular and molecular mechanisms involved with the malformation of the CC in these disorders remain undefined. Our current understanding of CC development is exclusively limited to factors and mechanisms involved with the early axon guidance phase, as well as those involved with the later myelination and synaptogenesis stages. However, the regulation of early postnatal CC refinement, in which initially produced callosal axons are selectively preserved or eliminated, remains completely unknown and is vastly understudied. Our major goal is to elucidate the mechanisms underlying the critical but vastly unexplored early postnatal processes governing CC development. This understanding will be crucial in shedding light on the pathogenesis of callosal abnormalities in neurodevelopmental disorders. Along with axon elimination, axon preservation is critical in maintaining the appropriate neuronal connections during this developmental refinement period, which leaves a lasting impact throughout the life of the organism. Our preliminary investigation has led to us to an intriguing hypothesis that the autism-linked gene, Plexin-A4, selectively preserves a subset of callosal axons during early postnatal CC refinement via the inhibition of caspase-mediated tubulin cleavage. In this proposed project, we will first establish the as-of-yet unconfirmed developmental elimination of callosal axons in the mouse CC (Aim 1). We will then test our hypothesis using various genetic and molecular biological techniques through our mouse model of CC refinement (Aim 2). We will then define molecular links between Plexin-A4 and caspase inhibition, a relationship which has previously been unknown, as well as identify novel autism-linked genes that are essential in the postnatal maintenance/elimination of callosal axons, using a unique combination of mass spectrometry and single-cell RNA sequencing (Aim 3). These results will, for the first time, validate the use of a mouse model to study the fundamental process of axon preservation during the postnatal refinement of the CC, and identify molecular pathways critical for this process. This novel study will also provide avenues for deciphering mechanisms underlying abnormal CC formation implicated in functional deficits associated with ASD and other neurodevelopmental disorders. Our results will open new avenues to therapeutic approaches by targeting these molecular pathways for abnormal CC development.

胼胝体(CC)提供认知和联想所必需的大脑半球间交流 过程，在几个更高级的功能中起关键作用，包括感觉处理，运动协调， 以及语言的习得和形成。CC畸形具有破坏性的功能后果； CC的发育不全和发育不全与几种与严重的神经和 认知障碍。此外，CC的解剖和生理缺陷也是常见的 在一些神经发育障碍中有报道，如自闭症谱系障碍(ASD)。然而，细胞 而与这些疾病中CC畸形有关的分子机制仍不清楚。我们的 目前对CC发展的理解仅限于与以下方面有关的因素和机制 早期轴突引导阶段，以及与后期髓鞘形成和突触发生有关的阶段。 然而，出生后早期CC精细化的调节，在其中最初产生的膝盖体轴突是 选择性地保存或消除，仍然是完全未知的，而且研究极少。我们的主要目标是 为了阐明关键但极未被探索的早期出生过程背后的机制 管理CC开发。这一认识将对揭示胼胝体的发病机制至关重要。 神经发育障碍的异常。随着轴突的消除，轴突的保存在 在这个发育精化期内保持适当的神经元连接，这就留下了一个 在生物体的整个生命过程中产生持久的影响。我们的初步调查得出了一个耐人寻味的结论 自闭症相关基因Plexin-A4在自闭症早期选择性地保留了一部分胼胝体轴突的假说 通过抑制caspase介导的微管蛋白切割来实现出生后CC的精细化。在这个拟议的项目中，我们 将首先建立到目前为止尚未证实的小鼠CC(AIM)内胼胝体轴突的发育消除 1)。然后，我们将通过我们的小鼠，使用各种遗传和分子生物学技术来验证我们的假设 CC求精模型(目标2)。然后我们将定义丛状蛋白-A4和半胱氨酸天冬氨酸酶抑制之间的分子联系， 一种以前未知的关系，以及识别与自闭症相关的新基因 使用独特的质量组合，在出生后维持/消除穹隆轴突方面是必不可少的 光谱分析和单细胞RNA测序(目标3)。这些结果将第一次验证使用 以小鼠为模型，研究生后精炼CC过程中轴突保留的基本过程， 并确定对这一过程至关重要的分子途径。这项新颖的研究也将为 与ASD相关的功能缺陷有关的CC形成异常的解释机制 以及其他神经发育障碍。我们的结果将为治疗方法开辟新的途径 以这些分子通路为靶点，研究CC的异常发育。