Reduced fertility and spermatogenesis defects in mice lacking chromosomal protein Hmgb2

Ronfani, Lorenza; Ferraguti, Marco; Croci, Laura; Ovitt, Catherine E.; Schöler, Hans R.; Consalez, G. Giacomo; Bianchi, Marco E.

doi:10.1242/dev.128.8.1265

Cited by 172 publications

(46 citation statements)

References 25 publications

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“…It has been proposed that the HMGA2 protein may be involved in chromatin condensation during G2/M transition of mouse spermatocytes by interacting with NEK2, which phosphorylates HMGA2 in a MAPK-dependent manner and release HMGA2 from chromatin ( Di Agostino et al 2004 ). Furthermore, deletion of Hmgb2 , encoding another member of the HMG protein family, showed spermatogenesis defects with subfertility suggesting a role in germ cell differentiation ( Ronfani et al 2001 ). Taken together, the data suggest a role for HMG proteins in male fertility where HMGB2 is required for spermatogonia function, while our data indicate that HMGA2 is required for normal-sized testis and sperm viability.…”

Section: Discussionmentioning

confidence: 99%

Hmga2 deficiency is associated with allometric growth retardation, infertility, and behavioral abnormalities in mice

Lee

Davis

et al. 2021

G3 Genes|Genomes|Genetics

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The high mobility group AT-hook 2 (HMGA2) protein works as an architectural regulator by binding AT-rich DNA sequences to induce conformational changes affecting transcription. Genomic deletions disrupting HMGA2 coding sequences and flanking non-coding sequences cause dwarfism in mice and rabbits. Here, CRISPR/Cas9 was used in mice to generate the Hmga2 null allele that specifically disrupts only the coding sequence. The loss of one or both alleles of Hmga2 resulted in reduced body size of 20% and 60%, respectively, compared to wild-type littermates as well as an allometric reduction in skull length in Hmga2-/- mice. Both male and female Hmga2-/- mice are infertile, whereas Hmga2+/- mice are fertile. Examination of reproductive tissues of Hmga2-/- males revealed a significantly reduced size of testis, epididymis, and seminal vesicle compared to controls, and 70% of knock-out males showed externalized penis, but no cryptorchidism was observed. Sperm analyses revealed severe oligospermia in mutant males and slightly decreased sperm viability, increased DNA damage but normal sperm chromatin compaction. Testis histology surprisingly revealed a normal seminiferous epithelium, despite the significant reduction in testis size. In addition, Hmga2-/- mice showed a significantly reduced exploratory behavior. In summary, the phenotypic effects in mouse using targeted mutagenesis confirmed that Hmga2 is affecting prenatal and postnatal growth regulation, male reproductive tissue development, and presents the first indication that Hmga2 function is required for normal mouse behavior. No specific effect, despite an allometric reduction, on craniofacial development was noted in contrast to previous reports of an altered craniofacial development in mice and rabbits carrying deletions of both coding and non-coding sequences at the 5’part of Hmga2.

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Section: Discussionmentioning

confidence: 99%

Hmga2 deficiency is associated with allometric growth retardation, infertility, and behavioral abnormalities in mice

Lee

Davis

et al. 2021

G3 Genes|Genomes|Genetics

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“…Moreover, HMGB2 has been reported to be essential in cellular senescence, chemotherapeutic and/or radiotherapy resistance, aging‐related diseases, and cancers (Krynetskaia, Phadke, Jadhav, & Krynetskiy, 2009; Shin et al, 2013; Syed et al, 2015; Taniguchi, Carames, Kawakami et al, 2009; Taniguchi, Carames, Ronfani et al, 2009; Wang et al, 2012; Wu et al, 2013). Although no fecundity phenotype was observed in the Hmgb2 −/− female mice (Ronfani et al, 2001), the function of HMGB2 in the ovary ageing and POI are still uncertain. In this study, HMGB2 was downregulated in GCs from early stage of ovarian failure.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐127‐5p impairs function of granulosa cells via HMGB2 gene in premature ovarian insufficiency

Zhang

Dang

Liu

et al. 2020

Journal Cellular Physiology

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Distinct microRNA (miRNA) profiles have been reported in premature ovarian insufficiency (POI), but their functional relevance in POI is not yet clearly stated. In this study, aberrant expressions of miR‐127‐5p and high mobility group box 2 (HMGB2) were observed by microarrays in granulosa cells (GCs) from biochemical POI (bPOI) women and further confirmed by a quantitative reverse‐transcription polymerase chain reaction. Immortalized human granulosa cell line and mouse primary ovarian GCs were used for functional validation. Orthotopic mouse model was established to examine the role of miR‐127‐5p in vivo. Finally, the expression of miR‐127‐5p was measured in the plasma of bPOI women. The receiver operating characteristic curve analysis was performed to determine the indicative role of miR‐127‐5p for ovarian reserve. Results showed the upregulation of miR‐127‐5p was identified in GCs from bPOI patients. It inhibited GCs proliferation and impaired DNA damage repair capacity through targeting HMGB2, which was significantly downregulated in GCs from the same cohort of cases. miR‐127‐5p was confirmed to attenuate DNA repair capability via HMGB2 in mouse ovary in vivo. Intriguingly, the upexpression of miR‐127‐5p was also detected in plasma of bPOI individuals, suggesting that miR‐127‐5p could be a promising indicator for bPOI. Taken together, our results discovered the deleterious effects of miR‐127‐5p on GCs function and its predictive value in POI process. The target gene HMGB2 could be considered as a new candidate for POI. This study highlights the importance of DNA repair capacity for ovarian function and sheds light on the epigenetic mechanism in the pathogenicity of POI.

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“…Hmgb2 is particularly common in the testis. Hmgb2−/− males have decreased fertility, which is associated with germ cell loss, spermatid abnormalities, and spermatozoa immobility [ 27 ]. During spermatogenesis, Col1a1 regulates the adherence of spermatogonia and preleptotene spermatocytes to the basement membrane, as well as their dissociation and migration into the lumen [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Integrated RNA-Seq Analysis Uncovers the Potential Mechanism of the “Kidney Governing Bones” Theory of TCM

Yang

Wang

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. As in philosophy of traditional Chinese medicine (TCM), the theory of “kidney governing bones” has been demonstrated by a series of scientific studies. Furthermore, many groups including ours have explored the molecular mechanisms related to bone development, growth, and regeneration using modern biology technologies, such as RNA sequencing (RNA-Seq) and isobaric tags for relative and absolute quantification (ITRAQ), and have demonstrated that the underlying molecular mechanisms were highly consistent with the “kidney governing bones” theory. Objective. Kidney-yang deficiency (YD), as a pathological condition, has a passive effect on the skeleton growth; more specifically, it is a state of skeletal metabolic disorder. However, the exact molecular mechanisms related to the “kidney governing bones” theory under the control of multiple organs and systems are still unknown. Methods. In this study, we performed RNA-Seq analysis to investigate and compare the gene expression patterns of six types of tissue (bone, cartilage, kidney, testicle, thyroid gland, and adrenal gland) from YD rats and normal rats and analyzed the interaction effects controlled by multiple functional genes and signaling pathways between those tissues. Results. Our results showed that, in the state of YD, the functions of bone and cartilage were inhibited. Furthermore, multiple organs involving the reproductive, endocrine, and urinary systems were also investigated, and our results showed that YD could cause dysfunctions of these systems by downregulating multiple functional genes and signaling pathways that positively regulate the homeostasis of these tissues. Conclusion. We ensure that “kidney governing bones” was not a simple change in a single gene but the changes in complex biological networks caused by functional changes in multiple genes. This also coincides with the holistic view of TCM, which holds that the human body itself is an organic whole and the functional activities of each organ coordinate with each other.

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Reduced fertility and spermatogenesis defects in mice lacking chromosomal protein Hmgb2

Cited by 172 publications

References 25 publications

Hmga2 deficiency is associated with allometric growth retardation, infertility, and behavioral abnormalities in mice

Hmga2 deficiency is associated with allometric growth retardation, infertility, and behavioral abnormalities in mice

MicroRNA‐127‐5p impairs function of granulosa cells via HMGB2 gene in premature ovarian insufficiency

Integrated RNA-Seq Analysis Uncovers the Potential Mechanism of the “Kidney Governing Bones” Theory of TCM

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