hnRNPA2B1 represses the disassembly of arsenite-induced stress granules and is essential for male fertility

Wang, Xiaoli; Fan, Xu; Zhang, Jin; Wang, Fengli; Chen, Jingshou; Wen, Yujiao; Wang, Lingjuan; Li, Tao; Li, Huaibiao; Gu, Heng; Zhang, Youzhi; Yuan, Shuiqiao

doi:10.1016/j.celrep.2024.113769

Cited by 4 publications

References 65 publications

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Sertoli cells require hnRNPC to support normal spermatogenesis and male fertility in mice

Mo,

Shu,

Cao

et al. 2024

Biology of Reproduction

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Sertoli cells (SCs) act as highly polarized testicular cells that nutritionally support multiple stages of germ cell development. However, the gene regulation network in SCs for modulating germ cell development has yet to be fully understood. In this study, we report that heterogeneous nuclear ribonucleoproteins C (hnRNPC) in SCs are essential for germ cell development and male fertility. Conditional knockout of hnRNPC in mouse SCs leads to aberrant SC proliferation, disrupted cytoskeleton of SCs, and compromised blood-testis barrier function, resulting in loss of supportive cell function and, ultimately, defective spermiogenesis in mice. Further RNA-seq analyses revealed these phenotypes are likely caused by the dysregulated genes in hnRNPC-deficient SCs related to cell adhesion, cell proliferation, and apoptotic process. In conclusion, this study demonstrates that hnRNPC plays a critical role in SCs for maintaining the function of SCs and sustaining steady-state spermatogenesis in mice.

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Sertoli cells require hnRNPC to support normal spermatogenesis and male fertility in mice

Mo,

Shu,

Cao

et al. 2024

Biology of Reproduction

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Cytoplasmic accumulation of a splice variant of hnRNPA2/B1 contributes to FUS-associated toxicity in a mouse model of ALS

Rossi,

Milani,

Della Valle

et al. 2024

Preprint

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Genetic and experimental findings point to a crucial role of RNA dysfunction in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Evidence suggests that mutations in RBPs such as FUS, a gene associated with ALS, affect the regulation of alternative splicing. We have previously shown that the overexpression of wild-type FUS in mice, a condition that induces ALS-like phenotypes, impacts the splicing of hnRNP A2/B1, a protein with key roles in RNA metabolism, suggesting that a pathological connection between FUS and hnRNP A2/B1 might promote FUS-associated toxicity. Here we report that the expression and distribution of different hnRNP A2/B1 splice variants are modified in the affected tissues of mice overexpressing wild-type FUS. Notably, degenerating motor neurons are characterized by the cytoplasmic accumulation of splice variants of hnRNP A2/B1 lacking exon 9 (hnRNP A2b/B1b).In vitrostudies show that exon 9 skipping affects the nucleocytoplasmic distribution of hnRNP A2/B1, promoting its localization into stress granules (SGs), and demonstrate that cytoplasmic localization is the primary driver of hnRNP A2b recruitment into SGs and cell toxicity. Finally, boosting exon 9 skipping using splicing switching oligonucleotides exacerbates disease phenotypes in wild-type FUS mice. Altogether, these findings reveal that alterations of the nucleocytoplasmic distribution of hnRNP A2/B1, driven by FUS-induced splicing changes, likely contribute to motor neuron degeneration in ALS.

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Knockdown of RUVBL2 improves hnRNPA2/B1‐stress granules dynamics to inhibit perioperative neurocognitive disorders in aged mild cognitive impairment rats

Wang,

Yang,

Wang

et al. 2024

Aging Cell

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Perioperative neurocognitive disorders (PND) is common in aged mild cognitive impairment (MCI) patients and can accelerate the progression to dementia. This process involves heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1)‐mediated aggregates of stress granules (SGs), while RUVBL2 influences the dynamics of these SGs. Our research explored a new target for modulating hnRNAPA2/B1‐SGs dynamics to accelerate their disassembly and potentially delay MCI progression due to PND. We assessed the effect of hippocampal RUVBL2 knockdown on hnRNPA2/B1‐SGs in aged MCI rats through behavioral studies, biochemical experiments and MRI. We also examined hnRNPA2/B1‐SGs dynamics using immunofluorescence staining and fluorescence recovery after photobleaching (FRAP) in rat primary hippocampal neurons. Our results revealed that hnRNPA2/B1 in the hippocampus of aged MCI rats translocates to the cytoplasm to form SGs following anesthesia. RUVBL2 knockdown promotes the disappearance of hnRNPA2/B1‐SGs, allowing hnRNPA2/B1 to return to the nucleus and enhancing functional activity in the brain regions of aged MCI rats. In primary hippocampal neurons, RUVBL2 deletion facilitated hnRNPA2/B1‐SGs transition from hydrogel to liquid, promoting disassembly. We compared three commonly used general anesthetics—3% sevoflurane, 40 mg·kg−1·h−1 propofol, and 9% desflurane. Sevoflurane upregulated RUVBL2, which decreased the intraneuronal pH and disrupted energy metabolism. These changes resulted in greater stabilization of hnRNPA2/B1‐ SGs. In conclusion, our findings indicated that the knockdown of RUVBL2 expression contributes to the transition of hnRNPA2/B1‐SGs from the hydrogel phase to the liquid phase. Targeted interference with RUVBL2 may represent a novel approach to delay the progression to dementia due to PND in aged MCI patients.

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hnRNPA2B1 represses the disassembly of arsenite-induced stress granules and is essential for male fertility

Cited by 4 publications

References 65 publications

Sertoli cells require hnRNPC to support normal spermatogenesis and male fertility in mice

Sertoli cells require hnRNPC to support normal spermatogenesis and male fertility in mice

Cytoplasmic accumulation of a splice variant of hnRNPA2/B1 contributes to FUS-associated toxicity in a mouse model of ALS

Knockdown of RUVBL2 improves hnRNPA2/B1‐stress granules dynamics to inhibit perioperative neurocognitive disorders in aged mild cognitive impairment rats

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