scholarly journals Motile cilia of the male reproductive system require miR-34/miR-449 for development and function to generate luminal turbulence

2019 ◽  
Vol 116 (9) ◽  
pp. 3584-3593 ◽  
Author(s):  
Shuiqiao Yuan ◽  
Yue Liu ◽  
Hongying Peng ◽  
Chong Tang ◽  
Grant W. Hennig ◽  
...  
Keyword(s):  
Rete Testis ◽  
Cell Surfaces ◽  
Efferent Duct ◽  
Genetic Ablation ◽  
Efferent Ductules ◽  
Mirna Clusters ◽  
Motile Cilia ◽  
And Function ◽  
Metachronal Waves ◽  
Immotile Spermatozoa

Cilia are cell-surface, microtubule-based organelles that project into extracellular space. Motile cilia are conserved throughout eukaryotes, and their beat induces the flow of fluid, relative to cell surfaces. In mammals, the coordinated beat of motile cilia provides highly specialized functions associated with the movement of luminal contents, as seen with metachronal waves transporting mucus in the respiratory tract. Motile cilia are also present in the male and female reproductive tracts. In the female, wave-like motions of oviductal cilia transport oocytes and embryos toward the uterus. A similar function has been assumed for motile cilia in efferent ductules of the male—i.e., to transport immotile sperm from rete testis into the epididymis. However, we report here that efferent ductal cilia in the male do not display a uniform wave-like beat to transport sperm solely in one direction, but rather exert a centripetal force on luminal fluids through whip-like beating with continual changes in direction, generating turbulence, which maintains immotile spermatozoa in suspension within the lumen. Genetic ablation of two miRNA clusters (miR-34b/c and -449a/b/c) led to failure in multiciliogenesis in murine efferent ductules due to dysregulation of numerous genes, and this mouse model allowed us to demonstrate that loss of efferent duct motile cilia causes sperm aggregation and agglutination, luminal obstruction, and sperm granulomas, which, in turn, induce back-pressure atrophy of the testis and ultimately male infertility.

scholarly journals Deficiency of the onco-miRNA cluster, miR-106b∼25, causes oligozoospermia and the cooperative action of miR-106b∼25 and miR-17∼92 is required to maintain male fertility

2020 ◽  
Vol 26 (6) ◽  
pp. 389-401
Author(s):  
Alicia Hurtado ◽  
Rogelio Palomino ◽  
Ina Georg ◽  
Miguel Lao ◽  
Francisca M Real ◽  
...  
Keyword(s):  
Male Fertility ◽  
Molecular Mechanisms ◽  
Mirna Cluster ◽  
Knock Out ◽  
Cooperative Action ◽  
Mouse Mutants ◽  
New Genes ◽  
Mirna Clusters ◽  
Testicular Histology ◽  
And Function

Abstract The identification of new genes involved in sexual development and gonadal function as potential candidates causing male infertility is important for both diagnostic and therapeutic purposes. Deficiency of the onco-miRNA cluster miR-17∼92 has been shown to disrupt spermatogenesis, whereas mutations in its paralog cluster, miR-106b∼25, that is expressed in the same cells, were reported to have no effect on testis development and function. The aim of this work is to determine the role of these two miRNA clusters in spermatogenesis and male fertility. For this, we analyzed miR-106b∼25 and miR-17∼92 single and double mouse mutants and compared them to control mice. We found that miR-106b∼25 knock out testes show reduced size, oligozoospermia and altered spermatogenesis. Transcriptomic analysis showed that multiple molecular pathways are deregulated in these mutant testes. Nevertheless, mutant males conserved normal fertility even when early spermatogenesis and other functions were disrupted. In contrast, miR-17∼92+/−; miR-106b∼25−/− double mutants showed severely disrupted testicular histology and significantly reduced fertility. Our results indicate that miR-106b∼25 and miR-17∼92 ensure accurate gene expression levels in the adult testis, keeping them within the required thresholds. They play a crucial role in testis homeostasis and are required to maintain male fertility. Hence, we have identified new candidate genetic factors to be screened in the molecular diagnosis of human males with reproductive disorders. Finally, considering the well-known oncogenic nature of these two clusters and the fact that patients with reduced fertility are more prone to testicular cancer, our results might also help to elucidate the molecular mechanisms linking both pathologies.

Insights into differentiation and function of the transition region between the seminiferous tubule and rete testis

2021 ◽  
Author(s):  
A.F.A. Figueiredo ◽  
Rex A. Hess ◽  
S.R. Batlouni ◽  
N.T. Wnuk ◽  
A.O. Tavares ◽  
...  
Keyword(s):  
Transition Region ◽  
Seminiferous Tubule ◽  
Rete Testis ◽  
And Function

scholarly journals p38δ genetic ablation protects female mice from anthracycline cardiotoxicity

2020 ◽  
Author(s):  
Sharon A George ◽  
Alexi Kiss ◽  
Sofian N Obaid ◽  
Aileen Venegas ◽  
Trisha Talapatra ◽  
...  
Keyword(s):  
Cardiac Injury ◽  
Mapk Signaling ◽  
Anthracycline Cardiotoxicity ◽  
Genetic Ablation ◽  
Female Mice ◽  
Echocardiographic Parameters ◽  
The Individual ◽  
And Function ◽  
First Time ◽  
Dose Dependent

ABSTRACTBACKGROUNDThe efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38γ and p38δ, remain uncharacterized.OBJECTIVESTo determine the potential cardioprotective effects of p38γ and p38δ genetic deletion in mice subjected to acute DOX treatment.METHODSMale and female wild-type (WT), p38γ-/-, p38δ-/- and p38γ-/-δ-/- mice were injected with 30 mg/kg DOX and their survival was tracked for ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining. Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy.RESULTSSignificantly improved survival was observed in p38δ-/- female mice post-DOX relative to WT females, but not in p38γ-/- or p38γ-/-δ-/- male or female mice. The improved survival in DOX-treated p38δ-/- females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38δ-/- females.CONCLUSIONSp38δ plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38δ targeting could be a potential cardioprotective strategy in anthracycline chemotherapy.NEW AND NOTEWORTHYThis study for the first time identifies the roles of the alternative p38γ and p38δ MAPK isoforms in promoting DOX-cardiotoxicity in a sex-specific manner. While p38γ systemic deletion did not affect DOX-cardiotoxicity, p38δ systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38δ-/- females and autophagy was increased.

Motile cilia structure and function in patients with mutations in the outer dynein arm heavy chain DNAH9

2018 ◽  
Author(s):  
Amelia Shoemark ◽  
Mahmoud R Fassad ◽  
Farheen Daudvohra ◽  
Tom Burgoyne ◽  
Robert A Hirst ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Structure And Function ◽  
Motile Cilia ◽  
And Function

scholarly journals The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease

2008 ◽  
Vol 205 (9) ◽  
pp. 2005-2017 ◽  
Author(s):  
Mark M.W. Chong ◽  
Jeffrey P. Rasmussen ◽  
Alexander Y. Rudensky ◽  
Dan R. Littman
Keyword(s):  
T Cell ◽  
Inflammatory Disease ◽  
Cell Types ◽  
Mirna Biogenesis ◽  
Cell Compartment ◽  
Foxp3 Gene ◽  
Genetic Ablation ◽  
And Function ◽  
Specific Deletion

MicroRNAs (miRNAs) are implicated in the differentiation and function of many cell types. We provide genetic and in vivo evidence that the two RNaseIII enzymes, Drosha and Dicer, do indeed function in the same pathway. These have previously been shown to mediate the stepwise maturation of miRNAs (Lee, Y., C. Ahn, J. Han, H. Choi, J. Kim, J. Yim, J. Lee, P. Provost, O. Radmark, S. Kim, and V.N. Kim. 2003. Nature. 425:415–419), and genetic ablation of either within the T cell compartment, or specifically within Foxp3+ regulatory T (T reg) cells, results in identical phenotypes. We found that miRNA biogenesis is indispensable for the function of T reg cells. Specific deletion of either Drosha or Dicer phenocopies mice lacking a functional Foxp3 gene or Foxp3+ cells, whereas deletion throughout the T cell compartment also results in spontaneous inflammatory disease, but later in life. Thus, miRNA-dependent regulation is critical for preventing spontaneous inflammation and autoimmunity.

Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1α in female mice

2017 ◽  
Vol 31 (1) ◽  
Author(s):  
Shailendra P. Singh ◽  
Ilana Grant ◽  
Aliza Meissner ◽  
Attallah Kappas ◽  
Nader G. Abraham
Keyword(s):  
Adipose Tissue ◽  
Knockout Mouse ◽  
Potential Role ◽  
Mitochondrial Quality Control ◽  
Knockout Mouse Model ◽  
Genetic Ablation ◽  
Beige Fat ◽  
And Function ◽  
White Fat

AbstractBackgroundHmox1 plays an important role in the regulation of mitochondrial bioenergetics and function by regulating cellular heme-derived CO and bilirubin. Previous studies have demonstrated that global disruption of HO-1 in humans and mice resulted in severe organ dysfunction.MethodsWe investigated the potential role of adipose-specific-HO-1 genetic ablation on adipose tissue function, mitochondrial quality control and energy expenditure by generating an adipo-HO-1 knockout mouse model (Adipo-HO-1ResultsAdipo-HO-1ConclusionAblation of adipose tissue-HO-1 abridged PGC1 expression promoted mitochondrial dysfunction and contributed to an increase of pro-inflammatory visceral fat and abrogated beige-cell like phenotype.

scholarly journals Effect of Deprival of Rete Testis Fluid on the Morphology of Efferent Ductules 1

1983 ◽  
Vol 29 (2) ◽  
pp. 525-534 ◽  
Author(s):  
B. W. Gray ◽  
B. G. Brown ◽  
V. K. Ganjam ◽  
J. F. Whitesides
Keyword(s):  
Rete Testis ◽  
Efferent Ductules

scholarly journals Zebrafish placenta-specific 8.1 (plac8.1) is required for motile cilia morphogenesis and function

2011 ◽  
Vol 356 (1) ◽  
pp. 152-153
Author(s):  
Haiting Ma ◽  
Cunxi Li ◽  
Robert Coffey ◽  
Lilianna Solnica-Krezel
Keyword(s):  
Motile Cilia ◽  
And Function

scholarly journals Type I Interferons Control Proliferation and Function of the Intestinal Epithelium

2016 ◽  
Vol 36 (7) ◽  
pp. 1124-1135 ◽  
Author(s):  
Yuliya V. Katlinskaya ◽  
Kanstantsin V. Katlinski ◽  
Audrey Lasri ◽  
Ning Li ◽  
Daniel P. Beiting ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Type I Interferons ◽  
Type I ◽  
Cell Renewal ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Antiproliferative Effects ◽  
Genetic Ablation ◽  
And Function ◽  
Intestinal Hyperplasia

Wnt pathway-driven proliferation and renewal of the intestinal epithelium must be tightly controlled to prevent development of cancer and barrier dysfunction. Although type I interferons (IFN) produced in the gut under the influence of microbiota are known for their antiproliferative effects, the role of these cytokines in regulating intestinal epithelial cell renewal is largely unknown. Here we report a novel role for IFN in the context of intestinal knockout of casein kinase 1α (CK1α), which controls the ubiquitination and degradation of both β-catenin and the IFNAR1 chain of the IFN receptor. Ablation of CK1α leads to the activation of both β-catenin and IFN pathways and prevents the unlimited proliferation of intestinal epithelial cells despite constitutive β-catenin activity. IFN signaling contributes to the activation of the p53 pathway and the appearance of apoptotic and senescence markers in the CK1α-deficient gut. Concurrent genetic ablation of CK1α and IFNAR1 leads to intestinal hyperplasia, robust attenuation of apoptosis, and rapid and lethal loss of barrier function. These data indicate that IFN play an important role in controlling the proliferation and function of the intestinal epithelium in the context of β-catenin activation.

scholarly journals Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

2021 ◽  
Author(s):  
Zhiyu Dai ◽  
Jianding Cheng ◽  
Bin Liu ◽  
Dan Yi ◽  
Anlin Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Adaptive Responses ◽  
Genetic Ablation ◽  
Pathological Cardiac Hypertrophy ◽  
And Function

Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. We observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Mice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) or tamoxifen-induced endothelial Egln1 deletion exhibited left ventricular hypertrophy and cardiac fibrosis. Genetic ablation and pharmacological inhibition of Hif2a but not Hif1a in endothelial Egln1 deficient mice normalized cardiac size and function. The present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2α dependent manner. Targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

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