Progression of spermatogonial differentiation in the mouse: the pathway to meiosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE155307 | GEO | 2020/07/29
REPOSITORIES: GEO
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Project description:Retinoic acid (RA) induces spermatogonial differentiation, but the mechanism by which it operates remains largely unknown. We developed a germ cell culture assay system to study genes involved in spermatogonial differentiation triggered by RA. Stimulated by Retinoic Acid 8 (Stra8), an RA-inducible gene, is indispensable for meiosis initiation, and its deletion results in a complete block of spermatogenesis at the pre-leptotene/zygotene stage due to failure to complete pre-meiotic DNA replication. To interrogate the role of Stra8 in RA mediated differentiation of spermatogonia, we derived germ cell cultures from the neonatal testis of both wild type and Stra8 knock-out mice. We provide the first evidence that Stra8 plays a crucial role in modulating the responsiveness of undifferentiated spermatogonia to RA and facilitates transition to a differentiated state. Stra8-mediated differentiation is achieved through downregulation of a large portfolio of genes and pathways, most notably including genes involved in the spermatogonial stem cell self-renewal process. We also report here for the first time the role of Transcription Elongation Regulator-1 Like (Tcerg1l) as a downstream effector of RA-induced spermatogonial differentiation.
2021-05-05 | GSE173873 | GEO
Project description:Spermatogonial differentiation is a developmental process that is essential for spermatogenesis, but the molecular and cellular changes that germ cells must undergo to transition from undifferentiated spermatogonia to differentiating spermatogonia remain largely undefined. Retinoic acid (RA) is necessary and sufficient for spermatogonial differentiation. Using the postnatal mouse testis, we examine the transcriptome changes that accompany spermatogonial differentiation. Spermatogenesis was synchronized by administration of potent and selective RA synthesis inhibitor; as a result, testes contained only undifferentiated spermatogonia. Then, the inhibitor was discontinued, and mice were given a single dose of exogenous RA to initiate spermatogonial differentiation. We measured transcriptomes in FACS-enriched germ cells either before RA administration, when the cells correspond to Aal spermatogonia (and a minor contribution of spermatogonial stem cells) or at two points after RA administration, when the cells correspond to A1 or A3 differentiating spermatogonia. The results of this study reveal the full transcriptome changes accompanying spermatogonial differentiation in the mouse.
2023-07-03 | GSE213716 | GEO
Project description:A bioenergetic balance between glycolysis and mitochondrial respiration is particularly important for stem cell fate specification. It however remains to be determined whether undifferentiated spermatogonia switch their preference of bioenergy production during differentiation. In this study, we found that ATP generation in spermatogonia was gradually increased upon retinoic acid-induced differentiation. To accommodate this elevated energy demand, retinoic acid signaling concomitantly switched ATP production in spermatogonia from glycolysis to mitochondrial respiration, accompanied by increased levels of reactive oxygen species. In addition, inhibition of glucose conversion to glucose-6-phosphate or pentose phosphate pathway blocked the formation of c-Kit+ differentiating germ cells, suggesting that metabolites produced from glycolysis are required for spermatogonial differentiation. We further demonstrated that the expression levels of several metabolic regulators and enzymes were significantly altered upon retinoic acid-induced differentiation by both RNA-seq analyses and quantitative proteomics. Taken together, our data unveil a critically regulated bioenergetic balance between glycolysis and mitochondrial respiration which is required for spermatogonial proliferation and differentiation.
2021-09-09 | PXD019136 | Pride
Project description:Defective germline reprogramming in Miwi2- and Dnmt3l-deficient mice results in the failure to reestablish transposon silencing, meiotic arrest and progressive loss of spermatogonia. Here we sought to understand the molecular basis for this spermatogonial dysfunction. Through a combination of imaging, conditional genetics and transcriptome analysis, we demonstrate that germ cell elimination in the respective mutants arises due to defective germline reprogramming rather than a function for the respective factors within spermatogonia. In both Miwi2-/- and Dnmt3l-/- spermatogonia the intracisternal-A particle (IAP) family of endogenous retroviruses is de-repressed, but in contrast to meiotic cells DNA damage is not observed. Instead we find that unmethylated IAP promoters rewire the spermatogonial transcriptome by driving expression of neighboring host genes. In summary, defective reprogramming deregulates the spermatogonial transcriptome that may underlie spermatogonial dysfunction.
2018-03-09 | E-MTAB-6202 | biostudies-arrayexpress
Project description:In mammals, a key transition in spermatogenesis is the exit from spermatogonial differentiation and mitotic proliferation and the entry into spermatocyte differentiation and meiosis. Although several genes that regulate this transition have been identified, how it is controlled and coordinated remains poorly understood. Here we examine the role in male gametogenesis of the Doublesex-related gene Dmrt6 (Dmrtb1) and find that Dmrt6 plays a critical role in directing germ cells through the mitotic to meiotic germ cell transition. DMRT6 protein is expressed in late mitotic spermatogonia. In mice of the C57BL/6J strain a null mutation in Dmrt6 disrupts spermatogonial differentiation, causing expression in inappropriate cell types of spermatogonial differentiation factors including SOHLH1, SOHLH2 and DMRT1 and the meiotic initiation factor STRA8 and causing most late spermatogonia to undergo apoptosis. In mice of the 129Sv background, most Dmrt6 mutant spermatogonia can complete differentiation and enter meiosis, but they show defects in chromosome pairing, establishment of the XY body, and processing of recombination foci, and mainly arrest in mid-pachynema. mRNA profiling of Dmrt6 mutant testes together with DMRT6 ChIP-seq suggest that DMRT6 represses genes involved in spermatogonial differentiation and activates genes required for meiotic prophase. Our results indicate that Dmrt6 plays a key role in coordinating the transition in gametogenic programs from spermatogonial differentiation and mitosis to spermatocyte development and meiosis. Six samples for RNA-Seq with three biological replicates in each group. Two samples for ChIP-Seq (one input and one ChIP).
2014-10-31 | E-GEOD-60440 | biostudies-arrayexpress
Project description:Using conditional knockout mice model, here we report the essential role of DIS3L2 in regulating male germline proliferation, growth and differentiation to ensure male fertility. We document that DIS3L2 is essential for spermatogonial homeostasis. DIS3L2-specific deletion in spermatogonia results in the reduction of the undifferentiated spermatogonial population and the block in transition to the differentiating stage in postnatal testes.
2021-07-15 | GSE160104 | GEO
Project description:Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The chromatin remodeling mechanisms underpinning early meiotic stages remain poorly understood. Here we focus on the function of one of the major autism genes, CHD8, in spermatogenesis, based on the epidemiological association between autism and low fertility rates. Specific ablation of Chd8 in germ cells results in gradual depletion of undifferentiated spermatogonia as well as failure of meiotic double strand formation followed by arrest at meiotic prophase I and cell death. Transcriptional analyses demonstrate that CHD8 is required for extensive activation of spermatogenic genes in spermatogonia, necessary for spermatogonial proliferation and meiosis. CHD8 directly binds to promoters of genes crucial for meiosis, including H3K4me3 histone methyltransferase genes, meiotic cohesin genes, HORMA domain containing genes, synaptonemal complex genes, and DNA damage response genes. Through transcriptionally regulating the interaction of these meiosis-related genes, we argue that CHD8 contributes to meiotic double strand break formation and subsequent meiotic progression. Our study uncovers an essential role of CHD8 for the proliferation of undifferentiated spermatogonia and the successful progression of meiotic prophase I.
2023-12-31 | GSE252121 | GEO
Project description:In mammals, a key transition in spermatogenesis is the exit from spermatogonial differentiation and mitotic proliferation and the entry into spermatocyte differentiation and meiosis. Although several genes that regulate this transition have been identified, how it is controlled and coordinated remains poorly understood. Here we examine the role in male gametogenesis of the Doublesex-related gene Dmrt6 (Dmrtb1) and find that Dmrt6 plays a critical role in directing germ cells through the mitotic to meiotic germ cell transition. DMRT6 protein is expressed in late mitotic spermatogonia. In mice of the C57BL/6J strain a null mutation in Dmrt6 disrupts spermatogonial differentiation, causing expression in inappropriate cell types of spermatogonial differentiation factors including SOHLH1, SOHLH2 and DMRT1 and the meiotic initiation factor STRA8 and causing most late spermatogonia to undergo apoptosis. In mice of the 129Sv background, most Dmrt6 mutant spermatogonia can complete differentiation and enter meiosis, but they show defects in chromosome pairing, establishment of the XY body, and processing of recombination foci, and mainly arrest in mid-pachynema. mRNA profiling of Dmrt6 mutant testes together with DMRT6 ChIP-seq suggest that DMRT6 represses genes involved in spermatogonial differentiation and activates genes required for meiotic prophase. Our results indicate that Dmrt6 plays a key role in coordinating the transition in gametogenic programs from spermatogonial differentiation and mitosis to spermatocyte development and meiosis.
2014-10-31 | GSE60440 | GEO
Project description:Despite the high incidence of male infertility, about 70% of infertile men do not receive a causative diagnosis. To gain insights into the regulatory mechanisms governing human germ cell function in normal and impaired spermatogenesis (crypto group), we combined single cell RNA sequencing (>30.000 cells), proteome, and histomorphometric analyses of testicular tissues. We found major alterations in the crypto spermatogonial compartment with increased numbers of the most undifferentiated spermatogonia (PIWIL4+ State 0 cells). We also observed a transcriptional switch within the spermatogonial compartment driven by the increased and prolonged expression of the transcription factor EGR4. Intriguingly, EGR4-regulated genes included the chromatin-associated transcriptional repressor UTF1, which was downregulated. Histomorphometrical analyses showed that these transcriptional changes were mirrored at the protein level and accompanied by a change in the chromatin structure of spermatogonia. This resulted in a reduction of Adark spermatogonia - characterized by tightly compacted chromatin and serving as reserve stem cells. These findings suggest that crypto patients are at a disadvantage especially in cases of gonadotoxic damage as they have less cells to help repopulate the testis. We hypothesize that the more relaxed chromatin status of spermatogonia is dependent on decreased UTF1 expression caused by EGR4 activation. These identified regulators of the spermatogonial compartment will be highly interesting targets to uncover genetic causes of male infertility.
2021-11-02 | PXD023979 | Pride
Project description:Here, gene profiles in rat spermatogonial stem cell lines are compared to publicly available mouse, monkey and human spermatogonial gene profiles. Interestingly, rat spermatogonia expressed metabolic control factors Foxa1, Foxa2 and Foxa3. Germline Foxa2 was enriched in Gfra1Hi and Gfra1Low undifferentiated A-single spermatogonia. Foxa2-bound loci in spermatogonial chromatin were over-represented by conserved stemness genes (Dusp6, Gfra1, Etv5, Rest, Nanos2, Foxp1) that intersect bioinformatically with conserved glutathione/pentose phosphate metabolism genes (Tkt, Gss, Gclc, Gclm, Gpx1, Gpx4, Fth), marking elevated spermatogonial GSH:GSSG. Cystine-uptake and intracellular conversion to cysteine typically couple glutathione biosynthesis to pentose phosphate metabolism. Rat spermatogonia, curiously, displayed poor germline stem cell viability in cystine-containing media, and, like primate spermatogonia, exhibited reduced transsulfuration pathway markers. Exogenous cysteine, cysteine-like mercaptans, somatic testis cells and ferroptosis inhibitors counteracted the cysteine starvation-induced spermatogonial death and stimulated spermatogonial growth factor activity in vitro.
2020-12-17 | GSE163302 | GEO