Subfertility in young male mice mutant for chromatin remodeler CECR2

Reproduction ◽  
2021 ◽  
Author(s):  
Kacie A Norton ◽  
Ross Humphreys ◽  
Chelsey Weatherill ◽  
Kevin Duong ◽  
Vivian V Nguyen ◽  
...  
Keyword(s):  
X Chromosome ◽  
Sex Chromosome ◽  
Young Male ◽  
Seminiferous Tubules ◽  
Testis Weight ◽  
Chromatin Remodelers ◽  
Male Subfertility ◽  
Meiotic Sex Chromosome Inactivation ◽  
Inappropriate Expression

Defects in spermatogenesis are an important cause of male infertility. Multiple aspects of spermatogenesis are controlled by chromatin remodelers, including regulating transcription. We previously described mutations in chromatin remodeling gene Cecr2 that resulted in the lethal neural tube defect exencephaly in most mutant mice, and subfertility in mice that were non-penetrant for exencephaly. Here, we show that the severity of male subfertility is dependent on age. Cecr2GT/Del males contain two mutant alleles, one of which is hypomorphic and therefore produces a small amount of protein. These males sire the fewest pups just after sexual maturity (88% fewer than Cecr2+/+ at P42-60) but improve with age (49% fewer than Cecr2+/+ at P81-100), although never completely recovering to Cecr2+/+ (wild type) levels. When young, they also have defects in testis histology, in vivo fertilization frequency, sperm number and motility, and testis weight that show similar improvement with age. Immunostaining of staged seminiferous tubules showed CECR2 in type A, In and B spermatogonia, and less in preleptotene and leptotene spermatocytes. Histological defects were first apparent in Cecr2GT/Del testes at P24, and RNA-seq analysis revealed 387 differentially expressed genes. This included 66 genes on the X chromosome (almost double the number on any other chromosome), all more highly expressed in Cecr2GT/Del testes. This inappropriate expression of X chromosome genes could be caused by a failure of effective meiotic sex chromosome inactivation. We identify several abnormally expressed genes that may contribute to defects in spermatogenesis at P24. Our results support a role for Cecr2 in juvenile spermatogenesis.

scholarly journals The mouse X chromosome is enriched for sex-biased genes not subject to selection by meiotic sex chromosome inactivation

2004 ◽  
Vol 36 (6) ◽  
pp. 642-646 ◽  
Author(s):  
Pavel P Khil ◽  
Natalya A Smirnova ◽  
Peter J Romanienko ◽  
R Daniel Camerini-Otero
Keyword(s):  
X Chromosome ◽  
Sex Chromosome ◽  
Chromosome Inactivation ◽  
Meiotic Sex Chromosome Inactivation ◽  
Sex Chromosome Inactivation

scholarly journals Dynamics of Meiotic Sex Chromosome Inactivation and Pachytene Activation in Mice Spermatogenesis

2019 ◽  
Author(s):  
Ábel Vértesy ◽  
Javier Frias-Aldeguer ◽  
Zeliha Sahin ◽  
Nicolas Rivron ◽  
Alexander van Oudenaarden ◽  
...  
Keyword(s):  
Single Molecule ◽  
Meiotic Prophase ◽  
Sex Chromosome ◽  
Chromosome Inactivation ◽  
Specific Gene ◽  
Prophase I ◽  
Meiotic Prophase I ◽  
Meiotic Sex Chromosome Inactivation ◽  
Sex Chromosome Inactivation

AbstractDuring germ cell development, cells undergo a drastic switch from mitosis to meiosis to form haploid germ cells. Sequencing and computational technologies now allow studying development at the single-cell level. Here we developed a multiplexed trajectory reconstruction to create a high-resolution developmental map of spermatogonia and prophase-I spermatocytes from testes of a Dazl-GFP reporter mouse. We identified three main transitions in the meiotic prophase-I: meiotic entry, the meiotic sex chromosome inactivation (MSCI), and concomitant pachytene activation. We validated the key features of these transitions in vivo using single molecule FISH. Focusing on MSCI, we found that 34% of sex chromosomal genes are induced shortly before MSCI, that silencing time is diverse and correlates with specific gene functions. These highlight a previously underappreciated level of regulation of MSCI. Finally, we found that spermatozoal genes in pachytene are activated in a temporal pattern reflecting the future anatomic and functional order of the sperm cell. Altogether we highlighted how precise and sequential changes in gene expression regulate cellular states in meiotic prophase-I.

scholarly journals The potential for a released autosomal X-shredder becoming a driving-Y chromosome and invasively suppressing wild populations of malaria mosquitoes

2019 ◽  
Author(s):  
Yehonatan Alcalay ◽  
Silke Fuchs ◽  
Roberto Galizi ◽  
Federica Bernardini ◽  
Roya Elaine Haghighat-Khah ◽  
...  
Keyword(s):  
Sex Ratio ◽  
Y Chromosome ◽  
X Chromosome ◽  
Sex Chromosome ◽  
Unexpected Event ◽  
Meiotic Sex Chromosome Inactivation ◽  
Ratio Distortion ◽  
High Fraction ◽  
Malaria Mosquitoes ◽  
Population Suppression

AbstractSynthetic sex-ratio distorters based on X-chromosome shredding are predicted to be more efficient than sterile males for population suppression of malaria mosquitoes using genetic control. X-chromosome shredding operates through the targeted elimination of X-chromosome-bearing gametes during male spermatogenesis, resulting in males that have a high fraction of male offspring. Strains harboring autosomal constructs containing a modified endonuclease I-PpoI have now been developed in the malaria mosquito Anopheles gambiae, resulting in strong sex-ratio distortion towards males. Data are being gathered for these strains for submission of regulatory dossiers for contained use and subsequent field release in West Africa. Since autosomal X-shredders are transmitted in a Mendelian fashion and can be selected against their frequency in the population is expected to decline once releases are halted. However, any unintended transfer of the X-shredder to the Y-chromosome could theoretically change these dynamics: This could lead to 100% transmission of the newly Y-linked X-shredder to the predominant male-biased offspring and its insulation from negative selection in females, resulting in its potential spread in the population and ultimately to suppression. Here, we analyze plausible mechanisms whereby an autosomal X-shredder could become linked to the Y-chromosome after release and provide data regarding its potential for activity should it become linked to the Y-chromosome. Our results strongly suggest that Y-chromosome linkage through remobilization of the transposon used for the initial genetic transformation is unlikely, and that, in the unexpected event that the X-shredder becomes linked to the Y-chromosome, expression and activity of the X-shredder would likely be inhibited by meiotic sex chromosome inactivation. We conclude that a functioning X-shredding-based Y-drive resulting from a naturally induced transposition or translocation of the transgene onto the Y-chromosome is unlikely.

scholarly journals On the Origin and Evolution of Drosophila New Genes during Spermatogenesis

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1796
Author(s):  
Qianwei Su ◽  
Huangyi He ◽  
Qi Zhou
Keyword(s):  
X Chromosome ◽  
Sex Chromosome ◽  
Expression Patterns ◽  
Cell Level ◽  
Origin And Evolution ◽  
Functional Studies ◽  
New Genes ◽  
Meiotic Sex Chromosome Inactivation ◽  
New Gene ◽  
Cell Transcriptome

The origin of functional new genes is a basic biological process that has significant contribution to organismal diversity. Previous studies in both Drosophila and mammals showed that new genes tend to be expressed in testes and avoid the X chromosome, presumably because of meiotic sex chromosome inactivation (MSCI). Here, we analyze the published single-cell transcriptome data of Drosophila adult testis and find an enrichment of male germline mitotic genes, but an underrepresentation of meiotic genes on the X chromosome. This can be attributed to an excess of autosomal meiotic genes that were derived from their X-linked mitotic progenitors, which provides direct cell-level evidence for MSCI in Drosophila. We reveal that new genes, particularly those produced by retrotransposition, tend to exhibit an expression shift toward late spermatogenesis compared with their parental copies, probably due to the more intensive sperm competition or sexual conflict. Our results dissect the complex factors including age, the origination mechanisms and the chromosomal locations that influence the new gene origination and evolution in testes, and identify new gene cases that show divergent cell-level expression patterns from their progenitors for future functional studies.

scholarly journals ARX/Arx is expressed in germ cells during spermatogenesis in both marsupial and mouse

Reproduction ◽  
2014 ◽  
Vol 147 (3) ◽  
pp. 279-289 ◽  
Author(s):  
Hongshi Yu ◽  
Andrew J Pask ◽  
Yanqiu Hu ◽  
Geoff Shaw ◽  
Marilyn B Renfree
Keyword(s):  
X Chromosome ◽  
Sex Chromosome ◽  
Neurological Diseases ◽  
Tammar Wallaby ◽  
Ambiguous Genitalia ◽  
Male Reproduction ◽  
Neural Cells ◽  
X Chromosomes ◽  
Adult Testis ◽  
Meiotic Sex Chromosome Inactivation

The X-linked aristaless gene,ARX, is essential for the development of the gonads, forebrain, olfactory bulb, pancreas, and skeletal muscle in mice and humans. Mutations cause neurological diseases, often accompanied by ambiguous genitalia. There are a disproportionately high number of testis and brain genes on the human and mouse X chromosomes. It is still unknown whether the X chromosome accrued these genes during its evolution or whether genes that find themselves on the X chromosome evolve such roles.ARXwas originally autosomal in mammals and remains so in marsupials, whereas in eutherian mammals it translocated to the X chromosome. In this study, we examined autosomalARXin tammars and compared it with the X-linkedArxin mice. We detectedARXmRNA in the neural cells of the forebrain, midbrain and hindbrain, and olfactory bulbs in developing tammars, consistent with the expression in mice.ARXwas detected by RT-PCR and mRNAin situhybridization in the developing tammar wallaby gonads of both sexes, suggestive of a role in sexual development as in mice. We also detectedARX/ArxmRNA in the adult testis in both tammars and mice, suggesting a potential novel role forARX/Arxin spermiogenesis.ARXtranscripts were predominantly observed in round spermatids.ArxmRNA localization distributions in the mouse adult testis suggest that it escaped meiotic sex chromosome inactivation during spermatogenesis. Our findings suggest thatARXin the therian mammal ancestor already played a role in male reproduction before it was recruited to the X chromosome in eutherians.

scholarly journals Loss of Ubiquitin Carboxy-Terminal Hydrolase L1 Impairs Long-Term Differentiation Competence and Metabolic Regulation in Murine Spermatogonial Stem Cells

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2265
Author(s):  
Whitney F. Alpaugh ◽  
Anna L. Voigt ◽  
Rkia Dardari ◽  
Lin Su ◽  
Iman Al Khatib ◽  
...  
Keyword(s):  
Stem Cells ◽  
Metabolic Regulation ◽  
Spermatogonial Stem Cells ◽  
Seminiferous Tubules ◽  
Testis Weight ◽  
Stem And Progenitor Cells ◽  
Cell Transcriptome ◽  
Carboxy Terminal

Spermatogonia are stem and progenitor cells responsible for maintaining mammalian spermatogenesis. Preserving the balance between self-renewal of spermatogonial stem cells (SSCs) and differentiation is critical for spermatogenesis and fertility. Ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) is highly expressed in spermatogonia of many species; however, its functional role has not been identified. Here, we aimed to understand the role of UCH-L1 in murine spermatogonia using a Uch-l1−/− mouse model. We confirmed that UCH-L1 is expressed in undifferentiated and early-differentiating spermatogonia in the post-natal mammalian testis. The Uch-l1−/− mice showed reduced testis weight and progressive degeneration of seminiferous tubules. Single-cell transcriptome analysis detected a dysregulated metabolic profile in spermatogonia of Uch-l1−/− compared to wild-type mice. Furthermore, cultured Uch-l1−/− SSCs had decreased capacity in regenerating full spermatogenesis after transplantation in vivo and accelerated oxidative phosphorylation (OXPHOS) during maintenance in vitro. Together, these results indicate that the absence of UCH-L1 impacts the maintenance of SSC homeostasis and metabolism and impacts the differentiation competence. Metabolic perturbations associated with loss of UCH-L1 appear to underlie a reduced capacity for supporting spermatogenesis and fertility with age. This work is one step further in understanding the complex regulatory circuits underlying SSC function.

scholarly journals DNA damage response protein TOPBP1 regulates X chromosome silencing in the mammalian germ line

2017 ◽  
Vol 114 (47) ◽  
pp. 12536-12541 ◽  
Author(s):  
Elias ElInati ◽  
Helen R. Russell ◽  
Obah A. Ojarikre ◽  
Mahesh Sangrithi ◽  
Takayuki Hirota ◽  
...  
Keyword(s):  
Dna Damage ◽  
X Chromosome ◽  
Sex Chromosome ◽  
Germ Line ◽  
Direct Interaction ◽  
Critical Factor ◽  
Dna Double Strand Breaks ◽  
Meiotic Silencing ◽  
Meiotic Sex Chromosome Inactivation ◽  
Meiotic Synapsis

Meiotic synapsis and recombination between homologs permits the formation of cross-overs that are essential for generating chromosomally balanced sperm and eggs. In mammals, surveillance mechanisms eliminate meiotic cells with defective synapsis, thereby minimizing transmission of aneuploidy. One such surveillance mechanism is meiotic silencing, the inactivation of genes located on asynapsed chromosomes, via ATR-dependent serine-139 phosphorylation of histone H2AFX (γH2AFX). Stimulation of ATR activity requires direct interaction with an ATR activation domain (AAD)-containing partner. However, which partner facilitates the meiotic silencing properties of ATR is unknown. Focusing on the best-characterized example of meiotic silencing, meiotic sex chromosome inactivation, we reveal this AAD-containing partner to be the DNA damage and checkpoint protein TOPBP1. Conditional TOPBP1 deletion during pachynema causes germ cell elimination associated with defective X chromosome gene silencing and sex chromosome condensation. TOPBP1 is essential for localization to the X chromosome of silencing “sensors,” including BRCA1, and effectors, including ATR, γH2AFX, and canonical repressive histone marks. We present evidence that persistent DNA double-strand breaks act as silencing initiation sites. Our study identifies TOPBP1 as a critical factor in meiotic sex chromosome silencing.

scholarly journals The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis

2019 ◽  
Author(s):  
Jordan P. Lewandowski ◽  
James C. Lee ◽  
Taeyoung Hwang ◽  
Hongjae Sunwoo ◽  
Jill M. Goldstein ◽  
...  
Keyword(s):  
Gene Expression ◽  
X Chromosome ◽  
Sex Chromosome ◽  
Noncoding Rnas ◽  
Regulatory Elements ◽  
Genetic Evidence ◽  
Loss Of Function ◽  
Lncrna Transcript ◽  
Dna And Rna

ABSTRACTRNA has been classically known to play central roles in biology, including maintaining telomeres1, protein synthesis2, and in sex chromosome compensation in certain species3,4. At the center of these important biological systems are noncoding RNAs. While thousands of long noncoding RNAs (lncRNAs) have been identified in mammalian genomes5–8, attributing RNA-based roles to lncRNA loci requires an assessment of whether the observed effect could be due to DNA regulatory elements, the act of transcription, or the lncRNA transcript. Here, we use the syntenically conserved lncRNA locus, Functional intergenic repeating RNA element (Firre), that is located on the X chromosome as a model to discriminate between DNA- and RNA-mediated effects in vivo. To this end, we generated genetically defined loss-of-function, gain-of-function, and rescue mouse models for Firre and provide genetic evidence that the Firre locus produces a trans-acting RNA. We report that: (i) Firre mutant mice have cell-specific defects during hematopoiesis and changes in gene expression that can be rescued by induction of Firre RNA from a transgene in the Firre knockout background, (ii) mice overexpressing Firre from a transgene exhibit increased levels of pro-inflammatory cytokines and impaired survival upon exposure to lipopolysaccharide, and (iii) deletion of the Firre locus did not result in changes in local gene expression on the X chromosome in 9 different biological contexts, suggesting that Firre does not function by cis-acting RNA or DNA elements. Together, our results provide genetic evidence that the Firre locus produces a trans-acting lncRNA that has physiological roles in hematopoiesis and immune function.

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