Cong Wan

Southern Medical University

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Xiaoyang Zhao

Henan Polytechnic University

Yaping Huang

China University of Mining and Technology

Mei Wang

Southern Medical University

Gang Chang

Shenzhen University Health Science Center

Ke Song

Southern Medical University

Xinyan Yang

Northeast Agricultural University

Jiexiang Zhao

Shandong Normal University

Manman Cui

Southern Medical University

Yi Zheng

First Affiliated Hospital of Wenzhou Medical University

Zhaokai Yao

Southern Medical University

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Southern Medical University

Chinese Academy of Sciences

Guangzhou Medical University

Peking University

Ministry of Education of the People's Republic of China

Huazhong University of Science and Technology

Shanghai Jiao Tong University

Wuhan University

University of Hong Kong

Guangzhou Institutes of Biomedicine and Health

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Peer Review #1 of "Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice (v0.1)"

Mei Wang Yaping Huang Han Wu Ke Song Cong Wan

Background.The NDUFS4 gene encodes an 18-kD subunit of mitochondria complex I , and mutations in this gene lead to the development of a severe neurodegenerative disease called Leigh syndrome (LS) in humans.To investigate the disease phenotypes and molecular mechanisms of Leigh syndrome, the Ndufs4 knockout (KO) mouse has been widely used as a novel animal model .Because the homozygotes cannot survive beyond child-bearing age , whether Ndufs4 and mitochondrial complex I influence early embryonic development remains unknown.In our study, we attempted to investigate embryonic development in Ndufs4 KO mice, which can be regarded as a Leigh disease model and were created through the CRISPR (clustered regularly interspaced short palindromic repeat) and Cas9 (CRISPR associated)-mediated genome editing system.Methods.We first designed a single guide RNA (sgRNA) targeting exon 2 of Ndufs4 to delete the NDUFS4 protein in mouse embryos to mimic Leigh syndrome.Then, we described the phenotypes of our mouse model by forced swimming and the open-field test as well as by assessing other behavioral characteristics.Intracytoplasmic sperm injection (ICSI) was performed to obtain KO embryos to test the influence of NDUFS4 deletion on early embryonic development. Results.In this study, we first generated Ndufs4 KO mice with physical and behavioral phenotypes similar to Leigh syndrome using the CRISPR/Cas9 system.The low developmental rate of KO embryos that were derived from knockout gametes indicated that the absence of NDUFS4 impaired the development of preimplantation embryos.Discussion.In this paper, we first obtained Ndufs4 KO mice that could mimic Leigh syndrome using the CRISPR/Cas9 system.Then, we identified the role of NDUFS4 in early embryonic development, shedding light on its roles in the respiratory chain and fertility.Our model provides a useful tool with which to investigate the function of Ndufs4.Although the pathological mechanisms of the disease need to be discovered, it helps to understand the pathogenesis of NDUFS4 deficiency in mice and its effects on human diseases.

Knockout mouse

10.7287/peerj.3339v0.1/reviews/1

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Cell-fate transition and determination analysis of mouse male germ cells throughout development

Nature Communications (2021)

Jiexiang Zhao Ping Lü Cong Wan Yaping Huang Manman Cui

Abstract Mammalian male germ cell development is a stepwise cell-fate transition process; however, the full-term developmental profile of male germ cells remains undefined. Here, by interrogating the high-precision transcriptome atlas of 11,598 cells covering 28 critical time-points, we demonstrate that cell-fate transition from mitotic to post-mitotic primordial germ cells is accompanied by transcriptome-scale reconfiguration and a transitional cell state. Notch signaling pathway is essential for initiating mitotic arrest and the maintenance of male germ cells’ identities. Ablation of HELQ induces developmental arrest and abnormal transcriptome reprogramming of male germ cells, indicating the importance of cell cycle regulation for proper cell-fate transition. Finally, systematic human-mouse comparison reveals potential regulators whose deficiency contributed to human male infertility via mitotic arrest regulation. Collectively, our study provides an accurate and comprehensive transcriptome atlas of the male germline cycle and allows for an in-depth understanding of the cell-fate transition and determination underlying male germ cell development.

Reprogramming

Cell fate determination

10.1038/s41467-021-27172-0

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Citations (58)

Exploration of the effect of Helq gene on stem cell pluripotency

Zhongguo Shiyan Dongwu Xuebao (2016)

Cong Wan Yaping Huang Mei Wang Xiao Yamei Zhao Xiaoyang

Source

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Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models

Nature Communications (2022)

Ke Song Xinyan Yang Geng An Xinyu Xia Jiexiang Zhao

Abstract Type 2 diabetes mellitus is one of the most prevalent metabolic diseases presenting with systemic pathologies, including reproductive disorders in male diabetic patients. However, the molecular mechanisms that contributing to spermatogenesis dysfunction in diabetic patients have not yet been fully elucidated. Here, we perform STRT-seq to examine the transcriptome of diabetic patients’ testes at single-cell resolution including all major cell types of the testis. Intriguingly, whereas spermatogenesis appears largely preserved, the gene expression profiles of Sertoli cells and the blood-testis barrier (BTB) structure are dramatically impaired. Among these deregulate pathways, the Apelin (APLN) peptide/Apelin-receptor (APJ) axis is hyper-activated in diabetic patients’ testes. Mechanistically, APLN is produced locally by Sertoli cells upon high glucose treatment, which subsequently suppress the production of carnitine and repress the expression of cell adhesion genes in Sertoli cells. Together, these effects culminate in BTB structural dysfunction. Finally, using the small molecule APLN receptor antagonist, ML221, we show that blocking APLN/APJ significantly ameliorate the BTB damage and, importantly, improve functional spermatogenesis in diabetic db/db mice. We also translate and validate these findings in cultured human testes. Our findings identify the APLN/APJ axis as a promising therapeutic target to improve reproduction capacity in male diabetic patients.

Apelin

10.1038/s41467-022-34990-3

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Single-cell multi-omics sequencing of human spermatogenesis reveals a DNA demethylation event associated with male meiotic recombination

Nature Cell Biology (2023)

Yaping Huang Lin Li Geng An Xinyan Yang Manman Cui

DNA demethylation

Demethylation

10.1038/s41556-023-01232-7

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HELQ deficiency impairs the induction of primordial germ cell‐like cells

FEBS Open Bio (2024)

Cong Wan Yaping Huang Xingguo Xue Gang Chang Mei Wang

Helicase POLQ‐like (HELQ) is a DNA helicase essential for the maintenance of genome stability. A recent study identified two HELQ missense mutations in some cases of infertile men. However, the functions of HELQ in the process of germline specification are not well known and whether its function is conserved between mouse and human remains unclear. Here, we revealed that Helq knockout ( Helq −/− ) could significantly reduce the efficiency of mouse primordial germ cell‐like cell (PGCLC) induction. In addition, Helq −/− embryonic bodies exhibited a severe apoptotic phenotype on day 6 of mouse PGCLC induction. p53 inhibitor treatment could partially rescue the generation of mouse PGCLCs from Helq mutant mouse embryonic stem cells. Finally, the genetic ablation of HELQ could also significantly impede the induction of human PGCLCs. Collectively, our study sheds light on the involvement of HELQ in the induction of both mouse and human PGCLCs, providing new insights into the mechanisms underlying germline differentiation and the genetic studies of human fertility.

RNA Helicase A

10.1002/2211-5463.13810

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Efficient generation of human primordial germ cell-like cells from pluripotent stem cells in a methylcellulose-based 3D system at large scale

PeerJ (2019)

Xiaoman Wang Tingting Liao Cong Wan Xiaoyu Yang Jiexiang Zhao

The mechanisms underlying human germ cell development and infertility remain largely unknown due to bioethical issues and the shortage of experimental materials. Therefore, an effective in vitro induction system of human primordial germ-like cells (hPGCLCs) from human pluripotent stem cells (hPSC) is in high demand. The current strategies used for the generation of hPGCLCs are not only costly but also difficult to perform at a large scale, thereby posing barriers to further research. In this study, we attempted to solve these problems by providing a new 3D culture system for hPGCLC differentiation.The efficiency and relative yield of a methylcellulose (MC)-based 3D hPGCLC induction system were first compared with that of a conventional U96 system. Then, we examined the gene expression of germ cell marker genes and the key epigenetic modifications of the EpCAM-/INTEGRINα6-high cells from the 3D MC induction system and the U96 system via quantitative PCR and immunofluorescence. Finally, the reliability of the MC-based 3D hPGCLC induction system was evaluated via the generation of induced pluripotent stem cells (iPSCs) from the testicular cells of one patient with obstructive azoospermia (OA) and followed by the subsequent differentiation of iPSCs into the germ cell lineage.In the present study, we demonstrated that the 3D MC induction system combined with low-cell attachment plates facilitated the generation of hPGCLCs at a large scale. We found that the hPGCLCs generated via the MC system shared similar characteristics to that via the U96 system in terms of the gene expression profiles, germ cell-specific markers, epigenetic modification states and cellular states. In addition, hPGCLCs from iPSCs derived from one OA patient were generated with high efficiency via the present 3D MC induction system.The in vitro induction of hPGCLCs from human embryonic stem cells (hESCs)/human induced pluripotent stem cells (hiPSCs) has significant implications in exploring the underlying mechanisms of the origin and specification of hPGCs and the epigenetic programming of the human germ line as well as treating male infertility. Here, we developed a simple and efficient 3D induction system to generate hPGCLCs from hESCs/hiPSCs at a large scale, which facilitated the study of human germ cell development and stem cell-based reproductive medicine.

Embryoid body

10.7717/peerj.6143

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Citations (13)

Peer Review #3 of "Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice (v0.1)"

Mei Wang Yaping Huang Han Wu Ke Song Cong Wan

Knockout mouse

10.7287/peerj.3339v0.1/reviews/3

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Dynamic transcriptomic and regulatory networks underpinning the transition from fetal primordial germ cells to spermatogonia in mice

Cell Proliferation (2024)

Jiexiang Zhao Kang Tang Gurong Jiang Xinyan Yang Manman Cui

Abstract The transition from fetal primordial germ cells (PGCs) to spermatogonia (SPG) is critical for male germ cell development; however, the detailed transcriptomic dynamics and regulation underlying this transition remain poorly understood. Here by interrogating the comprehensive transcriptome atlas dataset of mouse male germ cells and gonadal cells development, we elucidated the regulatory networks underlying this transition. Our single‐cell transcriptome analysis revealed that the transition from PGCs to SPG was characterized by global hypertranscription. A total of 315 highly active regulators were identified to be potentially involved in this transition, among which a non‐transcription factor (TF) regulator TAGLN2 was validated to be essential for spermatogonial stem cells (SSCs) maintenance and differentiation. Metabolism profiling analysis also revealed dynamic changes in metabolism‐related gene expression during PGC to SPG transition. Furthermore, we uncovered that intricate cell–cell communication exerted potential functions in the regulation of hypertranscription in germ cells by collaborating with stage‐specific active regulators. Collectively, our work extends the understanding of molecular mechanisms underlying male germ cell development, offering insights into the recapitulation of germ cell generation in vitro.

10.1111/cpr.13755

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Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice

PeerJ (2017)

Mei Wang Yaping Huang Han Wu Ke Song Cong Wan

The NDUFS4 gene encodes an 18-kD subunit of mitochondria complex I, and mutations in this gene lead to the development of a severe neurodegenerative disease called Leigh syndrome (LS) in humans. To investigate the disease phenotypes and molecular mechanisms of Leigh syndrome, the Ndufs4 knockout (KO) mouse has been widely used as a novel animal model. Because the homozygotes cannot survive beyond child-bearing age, whether Ndufs4 and mitochondrial complex I influence early embryonic development remains unknown. In our study, we attempted to investigate embryonic development in Ndufs4 KO mice, which can be regarded as a Leigh disease model and were created through the CRISPR (clustered regularly interspaced short palindromic repeat) and Cas9 (CRISPR associated)-mediated genome editing system.We first designed a single guide RNA (sgRNA) targeting exon 2 of Ndufs4 to delete the NDUFS4 protein in mouse embryos to mimic Leigh syndrome. Then, we described the phenotypes of our mouse model by forced swimming and the open-field test as well as by assessing other behavioral characteristics. Intracytoplasmic sperm injection (ICSI) was performed to obtain KO embryos to test the influence of NDUFS4 deletion on early embryonic development.In this study, we first generated Ndufs4 KO mice with physical and behavioral phenotypes similar to Leigh syndrome using the CRISPR/Cas9 system. The low developmental rate of KO embryos that were derived from knockout gametes indicated that the absence of NDUFS4 impaired the development of preimplantation embryos.In this paper, we first obtained Ndufs4 KO mice that could mimic Leigh syndrome using the CRISPR/Cas9 system. Then, we identified the role of NDUFS4 in early embryonic development, shedding light on its roles in the respiratory chain and fertility. Our model provides a useful tool with which to investigate the function of Ndufs4. Although the pathological mechanisms of the disease need to be discovered, it helps to understand the pathogenesis of NDUFS4 deficiency in mice and its effects on human diseases.

Knockout mouse

10.7717/peerj.3339

Cite

Citations (10)