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Frontiers in Aging 2021is a fly homologue of the mammalian SLC13A5 (mSLC13A5) plasma membrane citrate transporter, a key metabolic regulator and energy sensor involved in health, longevity,... (Review)
Review
is a fly homologue of the mammalian SLC13A5 (mSLC13A5) plasma membrane citrate transporter, a key metabolic regulator and energy sensor involved in health, longevity, and disease. Reduction of gene activity in flies, and its homologs in worms, modulates metabolism and extends longevity. The metabolic changes are similar to what is obtained with caloric restriction (dietary restriction). Similar effects on metabolism have been observed in mice and rats. As a citrate transporter, INDY regulates cytoplasmic citrate levels. flies heterozygous for a P-element insertion have increased spontaneous physical activity, increased fecundity, reduced insulin signaling, increased mitochondrial biogenesis, preserved intestinal stem cell homeostasis, lower lipid levels, and increased stress resistance. Mammalian knockout (-KO) mice have higher sensitivity to insulin signaling, lower blood pressure and heart rate, preserved memory and are protected from the negative effects of a high-fat diet and some of the negative effects of aging. Reducing expression in human hepatocarcinoma cells has recently been shown to inhibit cell proliferation. Reduced expression in the fly intestine affects intestinal stem cell proliferation, and has recently been shown to also inhibit germ cell proliferation in males with delayed sperm maturation and decreased spermatocyte numbers. These results highlight a new connection between energy metabolism and cell proliferation. The overrall picture in a variety of species points to a conserved role of INDY for metabolism and health. This is illustrated by an association of high gene expression with non-alcoholic fatty liver disease in obese humans. () coding region mutations (e.g., loss-of-function) are also associated with adverse effects in humans, such as autosomal recessive early infantile epileptic encephalopathy and Kohlschütter-Tönz syndrome. The recent findings illustrate the importance of gene for human health and disease. Furthermore, recent work on small-molecule regulators of INDY highlights the promise of INDY-based treatments for ameliorating disease and promoting healthy aging.
PubMed: 35822025
DOI: 10.3389/fragi.2021.782162 -
PLoS Genetics Jun 2023Transposable elements (TE) are mobile DNA sequences whose excessive proliferation endangers the host. Although animals have evolved robust TE-targeting defenses,...
Transposable elements (TE) are mobile DNA sequences whose excessive proliferation endangers the host. Although animals have evolved robust TE-targeting defenses, including Piwi-interacting (pi)RNAs, retrotransposon LINE-1 (L1) still thrives in humans and mice. To gain insights into L1 endurance, we characterized L1 Bodies (LBs) and ORF1p complexes in germ cells of piRNA-deficient Maelstrom null mice. We report that ORF1p interacts with TE RNAs, genic mRNAs, and stress granule proteins, consistent with earlier studies. We also show that ORF1p associates with the CCR4-NOT deadenylation complex and PRKRA, a Protein Kinase R factor. Despite ORF1p interactions with these negative regulators of RNA expression, the stability and translation of LB-localized mRNAs remain unchanged. To scrutinize these findings, we studied the effects of PRKRA on L1 in cultured cells and showed that it elevates ORF1p levels and L1 retrotransposition. These results suggest that ORF1p-driven condensates promote L1 propagation, without affecting the metabolism of endogenous RNAs.
Topics: Humans; Male; Mice; Animals; Retroelements; Ribonucleoproteins; Piwi-Interacting RNA; Spermatocytes; Long Interspersed Nucleotide Elements; RNA; RNA, Messenger; Cytoplasm; RNA, Small Interfering
PubMed: 37307272
DOI: 10.1371/journal.pgen.1010797 -
International Journal of Stem Cells Aug 2021Approximately 15% of couples suffer from infertility worldwide, and male factors contribute to about 30% of total sterility cases. However, there is little progress in...
Approximately 15% of couples suffer from infertility worldwide, and male factors contribute to about 30% of total sterility cases. However, there is little progress in treatments due to the obscured understanding of underlying mechanisms. Recently microRNAs have emerged as a key player in the process of spermatogenesis. Expression profiling of miR-181a was carried out in murine testes and spermatocyte culture system. cellular and biochemical assays were used to examine the effect of miR-181a and identify its target S6K1, as well as elucidate the function with chemical inhibitor of S6K1. Human testis samples analysis was employed to validate the findings. miR-181a level was upregulated during mouse spermatogenesis and knockdown of miR-181a attenuated the cell proliferation and G1/S arrest and increased the level of S6K1, which was identified as a downstream target of miR-181a. Overexpression of S6K1 also led to growth arrest of spermatocytes while inhibitor of S6K1 rescued the miR-181a knockdown-mediated cell proliferation defect. In human testis samples of azoospermia patients, low level of miR-181a was correlated with defects in the spermatogenic process. miR-181a is identified as a new regulator and high level of miR-181a contributes to spermatogenesis via targeting S6K1.
PubMed: 33906981
DOI: 10.15283/ijsc21001 -
Journal of Animal Science and... 2020Spermatogenesis is a complex differentiating developmental process in which undifferentiated spermatogonial germ cells differentiate into spermatocytes, spermatids, and... (Review)
Review
Spermatogenesis is a complex differentiating developmental process in which undifferentiated spermatogonial germ cells differentiate into spermatocytes, spermatids, and finally, to mature spermatozoa. This multistage developmental process of spermatogenesis involves the expression of many male germ cell-specific long noncoding RNAs (lncRNAs) and highly regulated and specific gene expression. LncRNAs are a recently discovered large class of noncoding cellular transcripts that are still relatively unexplored. Only a few of them have post-meiotic; however, lncRNAs are involved in many cellular biological processes. The expression of lncRNAs is biologically relevant in the highly dynamic and complex program of spermatogenesis and has become a research focus in recent genome studies. This review considers the important roles and novel regulatory functions whereby lncRNAs modulate mammalian spermatogenesis.
PubMed: 32128162
DOI: 10.1186/s40104-019-0424-8 -
World Journal of Clinical Cases Dec 2021Spermatocytic tumor is a rare, malignant neoplasm of the testes. Since the prognosis for this tumor type is favorable, accurate diagnosis and differentiation from other...
BACKGROUND
Spermatocytic tumor is a rare, malignant neoplasm of the testes. Since the prognosis for this tumor type is favorable, accurate diagnosis and differentiation from other malignant testicular neoplasms (classic seminoma and lymphoma) are crucial. To add to the existing literature on the diagnosis of spermatocytic tumor, herein we report the detailed clinical and histopathologic findings for a case that we encountered.
CASE SUMMARY
A 60-year-old Chinese man presented with a solid mass in the right scrotum. The mass was surgically removed and spermatocytic tumor was diagnosed. On microscopy, the tumor cells displayed an unusual arrangement in lobules, presenting a pseudo-glandular appearance. To summarize and compare the diagnostic features of this tumor and those of the differential diagnoses, we report our case findings and those mentioned in the literature for various testicular tumors. Although imaging methods can detect masses early in development, their diagnostic capabilities are limited. Biopsy, histopathology, and immunohistochemistry are necessary for confirmatory diagnosis.
CONCLUSION
It is important to identify and review the key diagnostic features of spermatocytic tumor.
PubMed: 35047626
DOI: 10.12998/wjcc.v9.i35.11115 -
Frontiers in Endocrinology 2023Cryopreservation of immature testicular tissue (ITT) is currently the only option to preserve fertility of prepubertal patients. Autologous transplantation of ITT may...
BACKGROUND
Cryopreservation of immature testicular tissue (ITT) is currently the only option to preserve fertility of prepubertal patients. Autologous transplantation of ITT may not be safe or appropriate for all patients. Therefore, methods to mature ITT are needed.
OBJECTIVES
Aim to investigate the feasibility of inducing spermatogenesis from ITT cryopreserved for pediatric patients prior to initiation of gonadotoxic therapy.
MATERIALS AND METHODS
Cryopreserved-thawed ITT from prepubertal and peripubertal patients were cultured for 7, 16, and 32 days in medium with no hormones or supplemented with 5 IU/L FSH, 1 IU/L hCG, or 5IU/L FSH+1 IU/L hCG. Samples were evaluated histologically to assess tissue integrity, and immunofluorescence staining was performed to identify VASA (DDX4)+ germ cells, UCHL1+ spermatogonia, SYCP3+ spermatocytes, CREM+ spermatids, SOX9+ Sertoli cells. Proliferation (KI67) and apoptosis (CASPASE3) of germ cells and Sertoli cells were also analyzed. Sertoli and Leydig cell maturation was evaluated by AR and INSL3 expression as well as expression of the blood testis barrier protein, CLAUDIN11, and testosterone secretion in the culture medium.
RESULTS
Integrity of seminiferous tubules, VASA+ germ cells and SOX9+ Sertoli cells were maintained up to 32 days. The number of VASA+ germ cells was consistently higher in the peripubertal groups. UCHL1+ undifferentiated spermatogonia and SOX9+ Sertoli cell proliferation was confirmed in most samples. SYCP3+ primary spermatocytes began to appear by day 16 in both age groups. Sertoli cell maturation was demonstrated by AR expression but the expression of CLAUDIN11 was disorganized. Presence of mature and functional Leydig cells was verified by INSL3 expression and secretion of testosterone. Gonadotropin treatments did not consistently impact the number or proliferation of germ cells or somatic cells, but FSH was necessary to increase testosterone secretion over time in prepubertal samples.
CONCLUSION
ITT were maintained in organotypic culture for up to 32 days and spermatogonia differentiated to produce primary spermatocytes in both pre- and peripubertal age groups. However, complete spermatogenesis was not observed in either group.
Topics: Male; Humans; Child; Fertility Preservation; Organ Culture Techniques; Cryopreservation; Testosterone; Follicle Stimulating Hormone
PubMed: 37701899
DOI: 10.3389/fendo.2023.1242263 -
Cells Feb 2023Long noncoding RNAs (lncRNAs) are regulatory transcripts in various biological processes. However, the role of lncRNAs in germline development remains poorly understood,...
Long noncoding RNAs (lncRNAs) are regulatory transcripts in various biological processes. However, the role of lncRNAs in germline development remains poorly understood, especially for fish primordial germ cell (PGC) development. In this study, the lncRNA profile of zebrafish PGC was revealed by single cell RNA-sequencing and bioinformatic prediction. We established the regulation network of lncRNA-mRNA associated with PGC development, from which we identified three novel lncRNAs-, , and -highly expressing in PGCs and gonads. Fluorescent in situ hybridization indicated germline-specific localization of and in the cytoplasm and nucleus of spermatogonia, spermatocyte, and occyte, and they were co-localized with vasa in the cytoplasm of the spermatogonia. By contrast, was localized in the cytoplasm of male germline, myoid cells and ovarian somatic cells. Loss- and gain-of-function experiments demonstrated that knockdown and PGC-specific overexpression of as well as universal overexpression of significantly disrupted PGC development. In summary, the present study revealed the lncRNA profile of zebrafish PGC and identified two novel lncRNAs associated with PGC development, providing new insights for understanding the regulatory mechanism of PGC development.
Topics: Male; Animals; Zebrafish; RNA, Long Noncoding; In Situ Hybridization, Fluorescence; Germ Cells; Zebrafish Proteins
PubMed: 36831339
DOI: 10.3390/cells12040672 -
IScience Sep 2023WNK1 is an important regulator in many physiological functions, yet its role in male reproduction is unexplored. In the male germline, WNK1 is upregulated in...
WNK1 is an important regulator in many physiological functions, yet its role in male reproduction is unexplored. In the male germline, WNK1 is upregulated in preleptotene spermatocytes indicating possible function(s) in spermatogenic meiosis. Indeed, deletion of in mid-pachytene spermatocytes using the mouse led to male sterility which resembled non-obstructive azoospermia in humans, where germ cells failed to complete spermatogenesis and produced no sperm. Mechanistically, we found elevated MTOR expression and signaling in the -depleted spermatocytes. As MTOR is a central mediator of translation, we speculated that translation may be accelerated in these spermatocytes. Supporting this, we found the acrosome protein, ACRBP to be prematurely expressed in the spermatocytes with deletion. Our study uncovered an MTOR-regulating factor in the male germline with potential implications in translation, and future studies will aim to understand how WNK1 regulates MTOR activity and impact translation on a broader spectrum.
PubMed: 37694147
DOI: 10.1016/j.isci.2023.107616 -
Science (New York, N.Y.) Mar 2024The extent to which prophage proteins interact with eukaryotic macromolecules is largely unknown. In this work, we show that cytoplasmic incompatibility factor A (CifA)...
The extent to which prophage proteins interact with eukaryotic macromolecules is largely unknown. In this work, we show that cytoplasmic incompatibility factor A (CifA) and B (CifB) proteins, encoded by prophage WO of the endosymbiont alter long noncoding RNA (lncRNA) and DNA during sperm development to establish a paternal-effect embryonic lethality known as cytoplasmic incompatibility (CI). CifA is a ribonuclease (RNase) that depletes a spermatocyte lncRNA important for the histone-to-protamine transition of spermiogenesis. Both CifA and CifB are deoxyribonucleases (DNases) that elevate DNA damage in late spermiogenesis. lncRNA knockdown enhances CI, and mutagenesis links lncRNA depletion and subsequent sperm chromatin integrity changes to embryonic DNA damage and CI. Hence, prophage proteins interact with eukaryotic macromolecules during gametogenesis to create a symbiosis that is fundamental to insect evolution and vector control.
Topics: Animals; Male; Cytoplasm; DNA; Prophages; RNA, Long Noncoding; Spermatozoa; Wolbachia; Paternal Inheritance; Viral Proteins; Drosophila melanogaster; Bacterial Proteins; Deoxyribonucleases
PubMed: 38452081
DOI: 10.1126/science.adk9469 -
Development (Cambridge, England) Nov 2022In mammalian testes, premeiotic spermatogonia respond to retinoic acid by completing an essential lengthy differentiation program before initiating meiosis. The...
In mammalian testes, premeiotic spermatogonia respond to retinoic acid by completing an essential lengthy differentiation program before initiating meiosis. The molecular and cellular changes directing these developmental processes remain largely undefined. This wide gap in knowledge is due to two unresolved technical challenges: (1) lack of robust and reliable in vitro models to study differentiation and meiotic initiation; and (2) lack of methods to isolate large and pure populations of male germ cells at each stage of differentiation and at meiotic initiation. Here, we report a facile in vitro differentiation and meiotic initiation system that can be readily manipulated, including the use of chemical agents that cannot be safely administered to live animals. In addition, we present a transgenic mouse model enabling fluorescence-activated cell sorting-based isolation of millions of spermatogonia at specific developmental stages as well as meiotic spermatocytes.
Topics: Male; Mice; Animals; Spermatogonia; Spermatogenesis; Spermatocytes; Testis; Meiosis; Cell Differentiation; Mice, Transgenic; Mammals
PubMed: 36250451
DOI: 10.1242/dev.200713