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

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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.