Development of intrasegmental vagus motor neuron subtype identity in DiGeorge Syndrome

迪乔治综合征节段内迷走运动神经元亚型识别的发展

• 批准号: 9337511
• 负责人: Gabrielle Russo Barsh
• 金额: $ 4.9万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9337511
• 关键词: 22q11 Deletion Syndrome; Address; Affect; Animals; Anterior; Architecture; Area; Axon; Birth; Brain; Branchial arch structure; CRISPR/Cas technology; Cell Nucleus; Cells; Cephalic; Child; Clinical; Congenital Abnormality; Cues; Data; Defect; Deglutition; Deglutition Disorders; Development; Developmental Biology; DiGeorge Syndrome; Disease; Event; Genetic; Head; Head and Neck Muscle; Head and neck structure; Health; Heart Abnormalities; Hereditary Disease; Heterozygote; Human; Human Genetics; Hypocalcemia result; Hypoparathyroidism; Incidence; Knock-out; Laryngeal muscle structure; Lead; Maps; Modeling; Molecular; Motor; Motor Neurons; Names; Nature; Neuraxis; Neurobiology; Neurologic; Neurologic Symptoms; Neurons; Patients; Peripheral; Pharmacology; Plant Roots; Population; Process; Proteins; Recording of previous events; Risk; Series; Shprintzen syndrome; Signal Transduction; Signaling Molecule; Specific qualifier value; Syndrome; System; T-Lymphocyte; Technology; Transplantation; Tretinoin; Tweens; Vagus nerve structure; Vertebrates; Visceral; Work; Zebrafish; base; developmental disease; experience; experimental study; genetic approach; hindbrain; imaging approach; insight; knock-down; microdeletion; pharynx muscle; public health relevance; transcription factor

 DESCRIPTION (provided by applicant): Despite the functional importance of the motor neurons that innervate the head and neck, the mechanisms regulating their development are still not well understood. In particular, the specification of motor neuron subtype identity withina single segment of the brain (rather than between different segments of the brain) in an unexplored area. The vagus motor neurons are a particularly interesting population because the cell bodies are contained in a single segment of the vertebrate hindbrain, called rhombomere 8, but peripherally the axons are highly segmented into five separate branches. In preliminary experiments using zebrafish as a model of vertebrate hindbrain development, I show that the vagus motor neurons are regionalized in the brain in a way that reflects the segmentation of their axons, such that multiple vagus motor neuron subtypes are present within rhombomere 8. This system therefore allows us to ask how motor neuron subtype identity is specified within a single segment of the hindbrain. Furthermore, it has been shown that vagus motor neurons, which in humans innervate the muscles of the larynx and pharynx, are abnormal in DiGeorge Syndrome, the most common microdeletion syndrome in humans. This proposal investigates how motor neuron subtype identity is affected in a zebrafish model of DiGeorge Syndrome. This has the potential to explain why patients DiGeorge Syndrome experience dysphagia, an important clinical problem whose mechanistic basis is unknown.

 描述（由申请人提供）：尽管支配头部和颈部的运动神经元的功能重要性，但调节其发育的机制仍不清楚。特别是，运动神经元亚型身份的规范在一个单一的大脑部分（而不是不同的大脑部分之间）在一个未开发的区域。迷走神经运动神经元是一个特别有趣的群体，因为细胞体包含在脊椎动物后脑的单个节段中，称为菱形节8，但外周轴突高度分段为五个独立的分支。在初步实验中使用斑马鱼作为脊椎动物后脑发育的模型，我表明，迷走神经运动神经元区域化的方式，反映了他们的轴突分割的大脑中，这样的多个迷走神经运动神经元亚型存在于菱形8。因此，这个系统允许我们询问运动神经元亚型身份是如何在后脑的单个片段内指定的。此外，已经表明，在人类中支配喉和咽的肌肉的迷走运动神经元在DiGeorge综合征（人类中最常见的微缺失综合征）中是异常的。该提案调查了运动神经元亚型身份如何在DiGeorge综合征的斑马鱼模型中受到影响。这有可能解释为什么DiGeorge综合征患者会出现吞咽困难，这是一个重要的临床问题，其机制基础尚不清楚。