Loss of MicroRNA-137 Impairs the Homeostasis of Potassium in Neurons via KCC2

Sun, Xiaowen; Wang, Zhimeng; Wang, Yingying; He, Xuan-Cheng; Liu, Cong; Zhang, Shuang-Feng; Du, Heng; Liu, Chang‐Mei; Teng, Zhao‐Qian

doi:10.5607/en19072

Cited by 5 publications

(3 citation statements)

References 70 publications

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“…Of particular interest is the association with epilepsy, which has been frequently reported in the patients with NDD [ 62 , 63 ]. Studies have shown that decreased expression of miR-137 is associated with epileptic phenotypes in brain tissues from patients and mouse models [ 64 , 65 ]. However, apparent epileptic seizures were not observed in the Mir137 –/– mouse model [ 17 ], suggesting that the MIR137 –/– miniature pig model may better illustrate the epileptic symptom seen in patients with NDD.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…In summary, our findings, for the first time, implicate the therapeutic potential of Agomir-137 in motor functional recovery after TBI. Given that miR-137 loss of function is responsible for the pathogeneses of several neurodevelopmental and neuropsychiatric disorders [60,61], it would be interesting to examine whether Agomir-137 administration is also beneficial for the treatment of these devastating diseases.…”

Section: Discussionmentioning

confidence: 99%

Early-Stage Application of Agomir-137 Promotes Locomotor Recovery in a Mouse Model of Motor Cortex Injury

Liu,

Teng

2023

IJMS

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Traumatic brain injury (TBI) is a significant risk factor for neurodegenerative disorders, and patients often experience varying degrees of motor impairment. MiR-137, a broadly conserved and brain-enriched miRNA, is a key regulator in neural development and in various neurological diseases. Following TBI, the expression of miR-137 is dramatically downregulated. However, whether miR-137 is a therapeutic target for TBI still remains unknown. Here, for the first time, we demonstrate that intranasal administration of miR-137 agomir (a mimic) in the early stage (0–7 days) of TBI effectively inhibits glial scar formation and improves neuronal survival, while early-stage administration of miR-137 antagomir (an inhibitor) deteriorates motor impairment. This study elucidates the therapeutic potential of miR-137 mimics in improving locomotor recovery following motor cortex injury.

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“…It is well known that miRNAs regulate a large number of genes, as is also the case for miR-137 ( 43 ). PDE10A , BDNF , and CACNA1C are other known targets of miR-137 ( 44 ). The human miR-137 host gene ( MIR137 ) has several common variants located within or near the gene on chromosome 1.…”

Section: Discussionmentioning

confidence: 99%

The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio

Holm

Possovre

Bandarabadi

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance The hypocretin (Hcrt, also known as orexin) neuropeptides regulate sleep and wake stability, and disturbances of Hcrt can lead to sleep disorders. MicroRNAs (miRNAs) are short noncoding RNAs that fine-tune protein expression levels, and miRNA-based therapeutics are emerging. We report a functional interaction between miRNA (miR-137) and Hcrt . We demonstrate that intracellular miR-137 levels in Hcrt neurons regulate Hcrt expression with downstream effects on wakefulness. Specifically, lowering of miR-137 levels increased wakefulness in mice. We further show that the miR-137:Hcrt interaction is conserved across mice and humans, that miR-137 also regulates sleep–wake balance in zebrafish, and that the MIR137 locus is genetically associated with sleep duration in humans. Together, our findings reveal an evolutionarily conserved sleep–wake regulatory role of miR-137.

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Loss of MicroRNA-137 Impairs the Homeostasis of Potassium in Neurons via KCC2

Cited by 5 publications

References 70 publications

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

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

Early-Stage Application of Agomir-137 Promotes Locomotor Recovery in a Mouse Model of Motor Cortex Injury

The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio

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