Nuclear microRNA-mediated transcriptional control determines adult microglial homeostasis and brain function

Li, Zhu; Mao, Kexin; Liu, Lin; Xu, Shengyun; Zeng, Min; Fu, Yu; Huang, Jintao; Li, Tingting; Gao, Guoan; Teng, Zhao-Qian; Sun, Qinmiao; Chen, Dahua; Cheng, Ying

doi:10.1016/j.celrep.2024.113964

Cited by 3 publications

(3 citation statements)

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“…This outcome was not unexpected as no patient with homozygous loss of MIR137 genes have been reported with 1p21.3 microdeletion [ 29 – 31 ]. Additionally, our previous study demonstrated that complete loss of miR-137, either in the germline or specific brain cell types, resulted in postnatal lethality in mouse models [ 17 , 32 ]. Moving forward, further efforts are necessary to generate heterozygous MIR137 KO miniature pigs and comprehensively assess their performance in behavioral assays related to core clinical symptoms of NDD.…”

Section: Discussionmentioning

confidence: 99%

“…The Diannan miniature pig fibroblast cell line and surrogate sows used in this study were raised at Laboratory Animal Centre of Yunnan Agricultural University. Mir137 + / + and Mir137 –/– mouse strains have been described previously [ 17 , 32 ]. All mice were kept on a 12-h light/dark cycle (7 a.m.–7 p.m. light period) and 55% humidity in a holding room maintained at a temperature of 22 ± 1 °C with ad libitum access to a standard pellet diet and water.…”

Section: Methodsmentioning

confidence: 99%

“…Conversely, clinical case reports have confirmed that patients with MIR137 heterozygous microdeletion (1p21.3 microdeletion) are all diagnosed with ID, and 90% of them exhibit clinical symptoms associated with ASD [ 29 – 31 ]. In our previous studies using mouse models, we observed that complete loss of miR-137, either in the germline or in specific brain cell types, resulted in postnatal lethality [ 17 , 32 ]. Additionally, partial loss of miR-137 was associated with impaired behavioral and cellular phenotypes linked to ASD [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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

Xu,

Wang,

Mao

et al. 2024

Cell Biosci

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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.

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