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

摘要(修订) NEXMIF是一个X连锁基因，其生物学功能鲜为人知。在人类中，NEXMIF的缺失会导致脑病，表现为大脑发育迟缓、沟通和记忆障碍、智力残疾和癫痫发作。在女性中，由于X染色体失活而导致的NEXMIF杂合表达导致了NEXMIF在大脑中的独特表达模式，导致了复杂的神经连接模式。在这项资助中，我们建议利用雌性小鼠来确定NEXMIF在大脑不同脑区的镶嵌表达的特征。我们计划将NEXMIF杂合子小鼠与含有X-连锁GFP的野生型小鼠品系杂交，这将使NEXMIF神经元的身份易于可视化以供分析。我们的目标是阐明单倍体缺陷雌性小鼠大脑中的细胞和分子失调，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是以非细胞自主的方式受到影响的；因此，我们将研究嵌合体神经元群体中的KO细胞对WT神经元的调节机制。这项研究的发现将为NEXMIF的神经生物学功能提供重要的原创性知识，这将有助于制定NEXMIF相关疾病的临床干预策略。

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.