Depletion of miR-96 Delays, But Does Not Arrest, Photoreceptor Development in Mice

Xiang, Lan; Zhang, Juan; Rao, Feng-Qin; Yang, Qiaoli; Zeng, Huiyi; Huang, Shenghai; Xie, Zhen-Xiang; Lv, Ji‐Neng; Lin, Dan-Dan; Chen, Xue-Jiao; Wu, Kun; Liu, Fan; Huang, Xiu‐Feng; Chen, Qi

doi:10.1167/iovs.63.4.24

Cited by 9 publications

(3 citation statements)

References 78 publications

(82 reference statements)

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“…Cep250 KO and age-matched control mice were paired for the RETI-port ERG system (Ganzfeld Q450 SC; Roland Consult, Brandenburg, Germany), and experiments were conducted as previously described. 28 In this study, these experiments were carried out in the afternoon. For dark-adaption, experimental mice were kept in the dark room for more than two hours and then anesthetized with a mixture of ketamine (100 mg/kg) and xylazine (10 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

“…ERG was conducted based on the protocol previously described. 28 The parameters of stimulation intensities for photopic responses were as follows: 0.20, 0.63, 2, 6.3, and 20 cd/m 2 . The parameters for scotopic responses were as follows: 0.0002, 0.0063, 0.20, 2, and 6.3 cd/m 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Optical coherence tomography (OCT) experiments were performed as previously described. 28 High-resolution spectral-domain OCT (Spectralis HRA + OCT; Heidelberg Engineering, Heidelberg, Germany) was usesd to obtain intraretinal layer images of experimental mice in the horizontal meridian centered on the optic nerve head. To prepare the mice for OCT experiments, their pupils were dilated, and the mice were anesthetized as in ERG experiments.…”

Section: Methodsmentioning

confidence: 99%

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Dysregulated Arginine Metabolism Is Linked to Retinal Degeneration in Cep250 Knockout Mice

Xiang,

Yang,

Xie

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose Degeneration of retinal photoreceptors is frequently observed in diverse ciliopathy disorders, and photoreceptor cilium gates the molecular trafficking between the inner and the outer segment (OS). This study aims to generate a homozygous global Cep250 knockout (KO) mouse and study the resulting phenotype. Methods We used Cep250 KO mice and untargeted metabolomics to uncover potential mechanisms underlying retinal degeneration. Long-term follow-up studies using optical coherence tomography (OCT) and electroretinography (ERG) were performed. Results OCT and ERG results demonstrated gradual thinning of the outer nuclear layer (ONL) and progressive attenuation of the scotopic ERG responses in Cep250 −/− mice. More TUNEL signal was observed in the ONL of these mice. Immunostaining of selected OS proteins revealed mislocalization of these proteins in the ONL of Cep250 −/− mice. Interestingly, untargeted metabolomics analysis revealed arginine-related metabolic pathways were altered and enriched in Cep250 −/− mice. Mis-localization of a key protein in the arginine metabolism pathway, arginase 1 (ARG1), in the ONL of KO mice further supports this model. Moreover, adeno-associated virus (AAV)-based retinal knockdown of Arg1 led to similar architectural and functional alterations in wild-type retinas. Conclusions Altogether, these results suggest that dysregulated arginine metabolism contributes to retinal degeneration in Cep250 −/− mice. Our findings provide novel insights that increase understanding of retinal degeneration in ciliopathy disorders.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Dysregulated Arginine Metabolism Is Linked to Retinal Degeneration in Cep250 Knockout Mice

Xiang,

Yang,

Xie

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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The miR‐669a‐5p/G3BP/HDAC6/AKAP12 Axis Regulates Primary Cilia Length

Wang,

Dai,

et al. 2023

Advanced Science

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Primary cilia are conserved organelles in most mammalian cells, acting as “antennae” to sense external signals. Maintaining a physiological cilium length is required for cilium function. MicroRNAs (miRNAs) are potent gene expression regulators, and aberrant miRNA expression is closely associated with ciliopathies. However, how miRNAs modulate cilium length remains elusive. Here, using the calcium‐shock method and small RNA sequencing, a miRNA is identified, namely, miR‐669a‐5p, that is highly expressed in the cilia‐enriched noncellular fraction. It is shown that miR‐669a‐5p promotes cilium elongation but not cilium formation in cultured cells. Mechanistically, it is demonstrated that miR‐669a‐5p represses ras‐GTPase‐activating protein SH3‐domain‐binding protein (G3BP) expression to inhibit histone deacetylase 6 (HDAC6) expression, which further upregulates A‐kinase anchor protein 12 (AKAP12) expression. This effect ultimately blocks cilia disassembly and leads to greater cilium length, which can be restored to wild‐type lengths by either upregulating HDAC6 or downregulating AKAP12. Collectively, these results elucidate a previously unidentified miR‐669a‐5p/G3BP/HDAC6/AKAP12 signaling pathway that regulates cilium length, providing potential pharmaceutical targets for treating ciliopathies.

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