Animal models of male subfertility targeted on LanCL1-regulated spermatogenic redox homeostasis

Huang, Chao; Yang, Chengcheng; Pang, Dejiang; Li, Chao; Gong, Huan; Cao, Xiyue; He, Xia; Chen, Xueyao; Mu, Bin; Cui, Yiyuan; Li, Wentao; Luo, Qihui; Cheng, Anchun; Jia, Lanlan; Chen, Mina; Xiao, Bo; Chen, Zhengli

doi:10.1038/s41684-022-00961-w

Cited by 3 publications

(18 citation statements)

References 82 publications

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“…Although it is an important cell in testosterone synthesis, most of the key rate-limiting enzymes of testosterone synthesis such as Cyp17a1, Cyp19a1, Hsd3b1, Srd5a1, Srd5a2 and Hsd17b3 were not remarkably different in the LanCL1 knockout mice. Moreover, the serum testosterone level had also no statistically significant differences, which was also consistent with the results of Huang et al [ 15 ]. Therefore, the LanCL1 gene would not influence the function of testosterone synthesis in the Leydig cell.…”

Section: Discussionsupporting

confidence: 91%

“…These were consistent with our results of immunofluorescence and single-cell RNAseq. Recently, Huang et al [ 15 ] performed a study about the LanCL1-regulated spermatogenic redox homeostasis, which had described the mechanisms of LanCL1 gene in influencing the male subfertility. After LanCL1 gene knockout, redox imbalance was observed in the testis with increased dihydroethidium-labeled ROS accumulation and a decreased NADPH/NADP ratio.…”

Section: Discussionmentioning

confidence: 99%

“…Lv et al [ 29 ] suggested that the overexpression of Lgals9 could promote the M2-type macrophages polarity. In the LanCL1 knockout mice, ROS and inflammation increased [ 15 ]. In order to maintain body homeostasis, the anti-inflammatory macrophage would increase.…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, we also found that oxidative damage in the brain of LanCL1 knockout mice could be alleviated by gut microbiota [ 14 ]. Recently, Huang et al [ 15 ] performed a mechanistic study, which found direct antioxidant activity of the LanCL1 gene in the mice spermatogenesis. However, no comprehensive landscape of all testicular cells and cell interactions after the LanCL1 gene knockout on the single-cell level had been described.…”

Section: Introductionmentioning

confidence: 99%

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Single-Cell RNAseq Resolve the Potential Effects of LanCL1 Gene in the Mouse Testis

Liao

Qin

et al. 2022

Cells

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Infertility affects lots of couples, half of which are caused by male factors. The LanCL1 gene is highly expressed in testis specifically, which might affect the development of sperms. In order to understand the potential functions of the LanCL1 gene in the testis, this study was conducted with constructed transgenic LanCL1 knockout mice. The mouse breeding experiment, semen analysis and single-cell RNAseq of testicular tissue were performed. Results suggested that the LanCL1 gene would significantly influence the reproduction ability and sperm motility of male mice. Single-cell RNAseq also confirmed the high expression of the LanCL1 gene in the spermatocytes and spermatids. Downregulating the LanCL1 gene expression could promote M2 macrophage polarity to maintain testicular homeostasis. Moreover, the LanCL1 gene could affect both the germ cells and stromal cells through various pathways such as the P53 signaling and the PPAR signaling pathway to disturb the normal process of spermatogenesis. However, no effects of the LanCL1 gene in testosterone synthesis and serum testosterone level were shown. Further studies are needed to discuss the mechanisms of the LanCL1 gene in the various cells of the testis independently.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Single-Cell RNAseq Resolve the Potential Effects of LanCL1 Gene in the Mouse Testis

Liao

Qin

et al. 2022

Cells

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“…However, most male mice lacking known antioxidant genes have no defects in testicular development or fertility [16][17][18][19][20][21][22][23][24], suggesting that testicular-specific and more important oxidative defense mechanisms remain to be discovered. Previously, we described a novel redox management system mediated by the SP1-LanCL1 axis, showing the essential role of LanCL1 in maintaining neuronal and testicular redox homeostasis [25,26]. LanCL1 has two other mammalian homologs, LanCL2 and LanCL3.…”

Section: Introductionmentioning

confidence: 99%

LanCL2 Implicates in Testicular Redox Homeostasis and Acrosomal Maturation

Zhao,

Wang,

Shi

et al. 2024

Antioxidants

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Redox balance plays an important role in testicular homeostasis. While lots of antioxidant molecules have been identified as widely expressed, the understanding of the critical mechanisms for redox management in male germ cells is inadequate. This study identified LanCL2 as a major male germ cell-specific antioxidant gene that is important for testicular homeostasis. Highly expressed in the brain and testis, LanCL2 expression correlates with testicular maturation and brain development. LanCL2 is enriched in spermatocytes and round spermatids of the testis. By examining LanCL2 knockout mice, we found that LanCL2 deletion did not affect postnatal brain development but injured the sperm parameters of adult mice. With histopathological analysis, we noticed that LanCL2 KO caused a pre-maturation and accelerated the self-renewal of spermatogonial stem cells in the early stage of spermatogenesis. In contrast, at the adult stage, LanCL2 KO damaged the acrosomal maturation in spermiogenesis, resulting in spermatogenic defects with a reduced number and motility of spermatozoa. Furthermore, we show that this disruption of testicular homeostasis in the LanCL2 KO testis was due to dysbalanced testicular redox homeostasis. This study demonstrates the critical role of LanCL2 in testicular homeostasis and redox balance.

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PGC-1α-Coordinated Hypothalamic Antioxidant Defense Is Linked to SP1-LanCL1 Axis during High-Fat-Diet-Induced Obesity in Male Mice

Shi,

Wang,

Gong

et al. 2024

Antioxidants

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High-fat-diet (HFD)-induced obesity parallels hypothalamic inflammation and oxidative stress, but the correlations between them are not well-defined. Here, with mouse models targeting the antioxidant gene LanCL1 in the hypothalamus, we demonstrate that impaired hypothalamic antioxidant defense aggravates HFD-induced hypothalamic inflammation and obesity progress, and these could be improved in mice with elevated hypothalamic antioxidant defense. We also show that peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a critical transcriptional coactivator, is implicated in regulating hypothalamic LanCL1 transcription, in collaboration with SP1 through a direct interaction, in response to HFD-induced palmitic acid (PA) accumulation. According to our results, when exposed to HFD, mice undergo a process of overwhelming hypothalamic antioxidant defense; short-time HFD exposure induces ROS production to activate PGC-1α and elevate LanCL1-mediated antioxidant defense, while long-time exposure promotes ubiquitin-mediated PGC-1α degradation and suppresses LanCL1 expression. Our findings show the critical importance of the hypothalamic PGC-1α-SP1-LanCL1 axis in regulating HFD-induced obesity, and provide new insights describing the correlations of hypothalamic inflammation and oxidative stress during this process.

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Animal models of male subfertility targeted on LanCL1-regulated spermatogenic redox homeostasis

Cited by 3 publications

References 82 publications

Single-Cell RNAseq Resolve the Potential Effects of LanCL1 Gene in the Mouse Testis

Single-Cell RNAseq Resolve the Potential Effects of LanCL1 Gene in the Mouse Testis

LanCL2 Implicates in Testicular Redox Homeostasis and Acrosomal Maturation

PGC-1α-Coordinated Hypothalamic Antioxidant Defense Is Linked to SP1-LanCL1 Axis during High-Fat-Diet-Induced Obesity in Male Mice

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