Study of NEXMIF mosaic expression on neuronal development and connectivity in female mice

NEXMIF 镶嵌表达对雌性小鼠神经元发育和连接的影响研究

基本信息

批准号：
10642436
负责人：
Hengye Man
金额：
$ 20.63万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-06 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642436
关键词：
Affect Age Autism Diagnosis Behavior Disorders Behavioral Biological Process Brain Brain region Cells Characteristics Clinical Communication Complex Cues Defect Dendrites Development Diagnosis Disease Encephalopathies Equilibrium Etiology Excitatory Postsynaptic Potentials Family Female Future Gene Dosage Genes Genetic Grant Growth Heterozygote High Prevalence Human Impairment In Vitro Individual Inherited Intellectual functioning disability Intervention Knock-out Knockout Mice Knowledge Laboratories Language Learning Link Mammalian Cell Measures Memory Memory impairment Microcephaly Molecular Morphology Mus Names Nature Neurites Neurobiology Neurons Patients Pattern Phenotype Population Process Reporting Rodent Model Seizures Signal Transduction Slice Social Interaction Societies Symptoms Synapses Synaptic Transmission Syndrome Testing Transgenic Organisms United States Vertebral column Visualization Wild Type Mouse Work X Chromosome X Inactivation autism spectrum disorder autistic behavioral phenotyping cost functional disability human female in vivo insight male migration mosaic mosaic pattern mouse model nerve supply neural network neural patterning neuron development neuropathology novel protein expression repetitive behavior sex synaptic function synaptogenesis therapeutic development

项目摘要

Abstract (Revised) NEXMIF is an X-linked gene with little known biological functions. Deletion of NEXMIF in humans results in encephalopathy demonstrating delayed brain development, impairments in communication and memory, intellectual disability and seizures. In females, heterozygous expression of NEXMIF due to X chromosome inactivation results in a unique pattern of NEXMIF expression in the brain, leading to complex patterns of neural connections. In this grant, we propose to utilize female mice to determine the features of mosaic expression of NEXMIF in the brain within various brain regions. We plan to cross the NEXMIF heterozygous mouse with wildtype mouse line that contains X-linked GFP, which will allow for easy visualization of the NEXMIF identities of neurons for analysis. We aim to elucidate the cellular and molecular dysregulations in the haploinsufficient female mouse brain, including neuronal morphology, synaptic protein expression, and input-specific alterations in synaptic transmission between the WT and KO neurons. Further, we find that neurons in the female transgenic brain are affected in a non-cell-autonomous manner; thus, we will examine the mechanisms by which the WT neurons are regulated by the KO cells in the mosaic neuronal population. Findings from this study will provide important original knowledge on the neurobiological function of NEXMIF, which will help with the development of strategies for clinical intervention in NEXMIF-related disorders.

摘要（修订） NexMIF是一个具有鲜为人知的生物学功能的X连锁基因。人类中Nexmif的缺失导致脑病表明大脑发育延迟，沟通和记忆力障碍，智力残疾和癫痫发作。在女性中，由于X染色体失活而引起的NexmiF的杂合表达导致脑中Nexmif表达的独特模式，从而导致神经连接的复杂模式。在这笔赠款中，我们建议利用雌性小鼠确定脑部在大脑区域内大脑中Nexmif的镶嵌表达的特征。我们计划使用包含X连锁GFP的Wildtype小鼠系穿越NexmiF杂合小鼠，这将允许对神经元的NexMIF身份轻松可视化进行分析。我们的目的是阐明雌性小鼠脑的细胞和分子失调，包括神经元形态，突触蛋白表达以及WT和KO神经元之间突触传递的输入特异性改变。此外，我们发现女性转基因大脑中的神经元受到非细胞自主的方式受到影响。因此，我们将检查镶嵌神经元种群中的KO细胞调节WT神经元的机制。这项研究的发现将提供有关NexMIF神经生物学功能的重要原始知识，这将有助于制定NEXMIF相关疾病的临床干预策略。