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Generation and transcriptomic characterization of MIR137 knockout miniature pig model for neurodevelopmental disorders

التفاصيل البيبلوغرافية
العنوان: Generation and transcriptomic characterization of MIR137 knockout miniature pig model for neurodevelopmental disorders
المؤلفون: Shengyun Xu, Jiaoxiang Wang, Kexin Mao, Deling Jiao, Zhu Li, Heng Zhao, Yifei Sun, Jin Feng, Yuanhao Lai, Ruiqi Peng, Yu Fu, Ruoyi Gan, Shuhan Chen, Hong-Ye Zhao, Hong-Jiang Wei, Ying Cheng
المصدر: Cell & Bioscience, Vol 14, Iss 1, Pp 1-15 (2024)
بيانات النشر: BMC, 2024.
سنة النشر: 2024
المجموعة: LCC:Biotechnology
LCC:Biology (General)
LCC:Biochemistry
مصطلحات موضوعية: Pig, Neurodevelopmental disorder, miR-137, Autism spectrum disorders, Intellectual disorders, Animal model, Biotechnology, TP248.13-248.65, Biology (General), QH301-705.5, Biochemistry, QD415-436
الوصف: Abstract Background Neurodevelopmental disorders (NDD), such as autism spectrum disorders (ASD) and intellectual disorders (ID), are highly debilitating childhood psychiatric conditions. Genetic factors are recognized as playing a major role in NDD, with a multitude of genes and genomic regions implicated. While the functional validation of NDD-associated genes has predominantly been carried out using mouse models, the significant differences in brain structure and gene function between mice and humans have limited the effectiveness of mouse models in exploring the underlying mechanisms of NDD. Therefore, it is important to establish alternative animal models that are more evolutionarily aligned with humans. Results In this study, we employed CRISPR/Cas9 and somatic cell nuclear transplantation technologies to successfully generate a knockout miniature pig model of the MIR137 gene, which encodes the neuropsychiatric disorder-associated microRNA miR-137. The homozygous knockout of MIR137 (MIR137 –/– ) effectively suppressed the expression of mature miR-137 and led to the birth of stillborn or short-lived piglets. Transcriptomic analysis revealed significant changes in genes associated with neurodevelopment and synaptic signaling in the brains of MIR137 –/– miniature pig, mirroring findings from human ASD transcriptomic data. In comparison to miR-137-deficient mouse and human induced pluripotent stem cell (hiPSC)-derived neuron models, the miniature pig model exhibited more consistent changes in critical neuronal genes relevant to humans following the loss of miR-137. Furthermore, a comparative analysis identified differentially expressed genes associated with ASD and ID risk genes in both miniature pig and hiPSC-derived neurons. Notably, human-specific miR-137 targets, such as CAMK2A, known to be linked to cognitive impairments and NDD, exhibited dysregulation in MIR137 –/– miniature pigs. These findings suggest that the loss of miR-137 in miniature pigs affects genes crucial for neurodevelopment, potentially contributing to the development of NDD. Conclusions Our study highlights the impact of miR-137 loss on critical genes involved in neurodevelopment and related disorders in MIR137 –/– miniature pigs. It establishes the miniature pig model as a valuable tool for investigating neurodevelopmental disorders, providing valuable insights for potential applications in human research.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2045-3701
Relation: https://doaj.org/toc/2045-3701
DOI: 10.1186/s13578-024-01268-8
URL الوصول: https://doaj.org/article/0e51734de2d9473fa312a94faec51e77
رقم الأكسشن: edsdoj.0e51734de2d9473fa312a94faec51e77
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:20453701
DOI:10.1186/s13578-024-01268-8