The essential roles of Mps1 in spermatogenesis and fertility in mice

AbstractMonopolar spindle 1 (MPS1), which plays a critical role in somatic mitosis, has also been revealed to be essential for meiosis I in oocytes. Spermatogenesis is an important process involving successive mitosis and meiosis, but the function of MPS1 in spermatogenesis remains unclear. Here, we generated Mps1 conditional knockout mice and found that Ddx4-cre-driven loss of Mps1 in male mice resulted in depletion of undifferentiated spermatogonial cells and subsequently of differentiated spermatogonia and spermatocytes. In addition, Stra8-cre-driven ablation of Mps1 in male mice led to germ cell loss and fertility reduction. Spermatocytes lacking Mps1 have blocked at the zygotene-to-pachytene transition in the prophase of meiosis I, which may be due to decreased H2B ubiquitination level mediated by MDM2. And the expression of many meiotic genes was decreased, while that of apoptotic genes was increased. Moreover, we also detected increased apoptosis in spermatocytes with Mps1 knockout, which may have been the reason why germ cells were lost. Taken together, our findings indicate that MPS1 is required for mitosis of gonocytes and spermatogonia, differentiation of undifferentiated spermatogonia, and progression of meiosis I in spermatocytes.

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The external mechanics of the chromosomes III-Meiosis in triploids

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1936.0066 ◽

1936 ◽

Vol 121 (823) ◽

pp. 290-300 ◽

Cited By ~ 2

Keyword(s):

Sexual Reproduction ◽

Chromosome Pairing ◽

Natural Experiment ◽

Diploid Species ◽

Homologous Chromosomes ◽

Normal Series ◽

Mitosis And Meiosis ◽

Meiosis I ◽

Prophase Of Meiosis ◽

The Way

Triploid organisms have three homologous chromosomes of each kind instead of the two of diploids. The regular mechanism of heredity fails in these circumstances. The triploid is incapable of breeding true by sexual reproduction. But the way in which it carries out the process of chromosome pairing and segregation is of great significance. The processes take place in normal series, but the relationships they establish are abnormal. A triploid thus provides a natural experiment, with the diploid of its own species as a control for one variable, and with triploids of different species as controls for others. In Tulipa and Hyacinthus I have made use of this experiment for inducing the principles of the external mechanics of chromosomes during the prophase of meiosis. I have inferred from them the relationships between the forces working in mitosis and meiosis. The triploid forms of various Fritillaria species make it possible to test the principles of metaphase mechanics induced from observations on structural hybrids and other polyploids (Darlington, 1932, b , and 1933, c ) as well as from the exceptional behaviour in the diploid species of Fritillaria already discussed.

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Reduced Levels of Drp1 Protect against Development of Retinal Vascular Lesions in Diabetic Retinopathy

Cells ◽

10.3390/cells10061379 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1379

Author(s):

Dongjoon Kim ◽

Hiromi Sesaki ◽

Sayon Roy

Keyword(s):

Diabetic Retinopathy ◽

Cell Loss ◽

Vascular Lesions ◽

Protective Effects ◽

Diabetic Mice ◽

Wild Type ◽

Apoptotic Genes ◽

Retinal Vascular Lesions ◽

Acellular Capillaries ◽

Pericyte Loss

High glucose (HG)-induced Drp1 overexpression contributes to mitochondrial dysfunction and promotes apoptosis in retinal endothelial cells. However, it is unknown whether inhibiting Drp1 overexpression protects against the development of retinal vascular cell loss in diabetes. To investigate whether reduced Drp1 level is protective against diabetes-induced retinal vascular lesions, four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Drp1+/− mice, and STZ-induced diabetic Drp1+/− mice were examined after 16 weeks of diabetes. Western Blot analysis indicated a significant increase in Drp1 expression in the diabetic retinas compared to those of WT mice; retinas of diabetic Drp1+/− mice showed reduced Drp1 level compared to those of diabetic mice. A significant increase in the number of acellular capillaries (AC) and pericyte loss (PL) was observed in the retinas of diabetic mice compared to those of the WT control mice. Importantly, a significant decrease in the number of AC and PL was observed in retinas of diabetic Drp1+/− mice compared to those of diabetic mice concomitant with increased expression of pro-apoptotic genes, Bax, cleaved PARP, and increased cleaved caspase-3 activity. Preventing diabetes-induced Drp1 overexpression may have protective effects against the development of vascular lesions, characteristic of diabetic retinopathy.

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Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice

Neural Plasticity ◽

10.1155/2017/4526417 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Hua Yang ◽

Mengjie Zhang ◽

Jiahao Shi ◽

Yunhe Zhou ◽

Zhipeng Wan ◽

...

Keyword(s):

Cerebral Cortex ◽

Mouse Model ◽

Glutamate Release ◽

Critical Role ◽

Conditional Knockout ◽

Snare Complex ◽

Extracellular Glutamate ◽

Glutamate Level

Several studies have associated reduced expression of synaptosomal-associated protein of 25 kDa (SNAP-25) with schizophrenia, yet little is known about its role in the illness. In this paper, a forebrain glutamatergic neuron-specific SNAP-25 knockout mouse model was constructed and studied to explore the possible pathogenetic role of SNAP-25 in schizophrenia. We showed that SNAP-25 conditional knockout (cKO) mice exhibited typical schizophrenia-like phenotype. A significantly elevated extracellular glutamate level was detected in the cerebral cortex of the mouse model. Compared with Ctrls, SNAP-25 was dramatically reduced by about 60% both in cytoplasm and in membrane fractions of cerebral cortex of cKOs, while the other two core members of SNARE complex: Syntaxin-1 (increased ~80%) and Vamp2 (increased ~96%) were significantly increased in cell membrane part. Riluzole, a glutamate release inhibitor, significantly attenuated the locomotor hyperactivity deficits in cKO mice. Our findings provide in vivo functional evidence showing a critical role of SNAP-25 dysfunction on synaptic transmission, which contributes to the developmental of schizophrenia. It is suggested that a SNAP-25 cKO mouse, a valuable model for schizophrenia, could address questions regarding presynaptic alterations that contribute to the etiopathophysiology of SZ and help to consummate the pre- and postsynaptic glutamatergic pathogenesis of the illness.

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AKT1-CREB stimulation of PDGFRα expression is pivotal for PTEN deficient tumor development

Cell Death and Disease ◽

10.1038/s41419-021-03433-0 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Xiaofeng Wan ◽

Meng Zhou ◽

Fuqiang Huang ◽

Na Zhao ◽

Xu Chen ◽

...

Keyword(s):

Signaling Pathway ◽

Human Cancer ◽

Critical Role ◽

Tumor Development ◽

Growth Factor Receptor ◽

Conditional Knockout ◽

Loss Of Function ◽

Akt Inhibitor ◽

Human Cancer Cell Lines ◽

Direct Binding

AbstractAs evidenced by the behavior of loss-of-function mutants of PTEN in the context of a gain-of-function mutation of AKT1, the PTEN-AKT1 signaling pathway plays a critical role in human cancers. In this study, we demonstrated that a deficiency in PTEN or activation of AKT1 potentiated the expression of platelet-derived growth factor receptor α (PDGFRα) based on studies on Pten−/− mouse embryonic fibroblasts, human cancer cell lines, the hepatic tissues of Pten conditional knockout mice, and human cancer tissues. Loss of PTEN enhanced PDGFRα expression via activation of the AKT1-CREB signaling cascade. CREB transactivated PDGFRα expression by direct binding of the promoter of the PDGFRα gene. Depletion of PDGFRα attenuated the tumorigenicity of Pten-null cells in nude mice. Moreover, the PI3K-AKT signaling pathway has been shown to positively correlate with PDGFRα expression in multiple cancers. Augmented PDGFRα was associated with poor survival of cancer patients. Lastly, combination treatment with the AKT inhibitor MK-2206 and the PDGFR inhibitor CP-673451 displayed synergistic anti-tumor effects. Therefore, activation of the AKT1-CREB-PDGFRα signaling pathway contributes to the tumor growth induced by PTEN deficiency and should be targeted for cancer treatment.

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Abstract 041: mTORC1 is Required for Leptin-induced Sympathetic Activation to the Kidney but Not Brown Adipose Tissue

Hypertension ◽

10.1161/hyp.68.suppl_1.041 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Balyssa B Bell ◽

Donald A Morgan ◽

Kamal Rahmouni

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Molecular Mechanisms ◽

Leptin Receptor ◽

Critical Role ◽

Conditional Knockout ◽

Sympathetic Activation ◽

Long Term Effects ◽

Brown Adipose ◽

Mtorc1 Signaling

The adipocyte-derived hormone leptin plays a critical role in the regulation of energy homeostasis through its action in the brain to decrease food intake and promote energy expenditure by increasing sympathetic nerve activity (SNA) to the thermogenic brown adipose tissue (BAT). Leptin also increases SNA to cardiovascular organs including the kidney and raises arterial pressure. However, it is unclear whether leptin controls regional SNA via conserved or distinct molecular mechanisms. Multiple intracellular pathways have been associated with leptin signaling including the mechanistic target of rapamycin complex 1 (mTORC1), which has been proposed as a critical determinant of leptin action. Here, we assessed the contribution of mTORC1 signaling to leptin-evoked regional sympathetic activation. Simultaneous multifiber recording of renal and BAT SNA in anesthetized C57BL/6J mice showed that intracerebroventricular (ICV) administration of leptin (2μg, n=5) increased both renal (170±34%) and BAT (208±37%) SNA. Interestingly, ICV pre-treatment with the mTORC1 inhibitor (rapamycin, 5ng, n=6) abolished the leptin-induced increase in renal (10±6%, P<0.05 vs controls) but not BAT (226±31%) SNA. Next, we used conditional knockout mice that lack the critical mTORC1 subunit, Raptor, specifically in leptin receptor (LRb)-expressing cells (LRb Cre /Raptor fl/fl ) to determine the long-term effects of disrupting mTORC1 signaling on leptin-evoked increase in regional SNA. We confirmed the inability of leptin to activate mTORC1 signaling in LRb-expressing cells of LRb Cre /Raptor fl/fl mice relative to controls using immunohistochemical staining of phosphorylated ribosomal S6, a downstream target of mTORC1. We observed a significant increase in renal SNA in response to ICV leptin in control mice (127±16%, n=9), but not in LRb Cre /Raptor fl/fl mice (-4±15%, n=9, P<0.05 vs controls). Conversely, ICV leptin-induced increase in BAT SNA was not different in LRb Cre /Raptor fl/fl mice (109±27%, n=5) vs. littermate controls (173±52%, n=4). Our data suggest a critical role for mTORC1 signaling in selectively mediating the cardiovascular sympathetic but not the thermogenic actions of leptin, with important implications for obesity-associated hypertension.

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Toll-9 interacts with Toll-1 to mediate a feedback loop during apoptosis-induced proliferation in Drosophila

10.1101/2020.10.19.346254 ◽

2020 ◽

Author(s):

Alicia Shields ◽

Alla Amcheslavsky ◽

Elizabeth Brown ◽

Yingchao Nie ◽

Takahiro Tanji ◽

...

Keyword(s):

Nuclear Translocation ◽

Apoptotic Cell ◽

Cell Loss ◽

Cell Competition ◽

General Role ◽

Compensatory Proliferation ◽

Amplification Loop ◽

Apoptotic Genes ◽

Necessary And Sufficient ◽

Related Proteins

AbstractDrosophila Toll-1 and all mammalian Toll-like receptors regulate innate immunity. However, the functions of the remaining eight Toll-related proteins in Drosophila are not fully understood. Here, we show that Drosophila Toll-9 is necessary and sufficient for a special form of compensatory proliferation after apoptotic cell loss (undead apoptosis-induced proliferation (AiP)). Mechanistically, for AiP, Toll-9 interacts with Toll-1 to activate the intracellular Toll-1 pathway for nuclear translocation of the NF-κB-like transcription factor Dorsal which induces expression of the pro-apoptotic genes reaper and hid. This activity contributes to the feedback amplification loop that operates in undead cells. Given that Toll-9 also functions in loser cells during cell competition, we define a general role of Toll-9 in cellular stress situations leading to the expression of pro-apoptotic genes which trigger apoptosis and apoptosis-induced processes such as AiP. This work identifies conceptual similarities between cell competition and AiP.

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Mps1 promotes poleward chromosome movements in meiotic pro-metaphase

10.1101/2020.06.28.176370 ◽

2020 ◽

Author(s):

Régis E Meyer ◽

Aaron R Tipton ◽

Gary J Gorbsky ◽

Dean S Dawson

Keyword(s):

Chromosome Pair ◽

Single Unit ◽

Spindle Pole ◽

Microtubule Depolymerization ◽

Data Support ◽

Chromosome Movements ◽

Meiosis I ◽

Prophase Of Meiosis

ABSTRACTIn prophase of meiosis I, homologous partner chromosomes pair and become connected by crossovers. Chiasmata, the connections formed between the partners enable the chromosome pair, called a bivalent, to attach as a single unit to the spindle. When the meiosis I spindle forms in prometaphase, most bivalents are associated with a single spindle pole and go through a series of oscillations on the spindle, attaching to and detaching from microtubules until the partners of the bivalent are bi-oriented, that is, attached to microtubules from opposite sides of the spindle, and prepared to be segregated at anaphase I. The conserved, kinetochore-associated kinase, Mps1, is essential for the bivalents to be pulled by microtubules across the spindle in prometaphase. Here we show that MPS1 is not required for kinetochores to attach microtubules but instead is necessary to trigger the migration of microtubule-attached kinetochores towards the poles. Our data support the model that Mps1 triggers depolymerization of microtubule ends once they attach to kinetochores in prometaphase. Thus, Mps1 acts at the kinetochore to co-ordinate the successful attachment of a microtubule and the triggering of microtubule depolymerization to move the chromosome.

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Klp2 and Ase1 synergize to maintain meiotic spindle stability during metaphase I

10.1101/2020.01.31.929729 ◽

2020 ◽

Author(s):

Fan Zheng ◽

Fenfen Dong ◽

Shuo Yu ◽

Tianpeng Li ◽

Yanze Jian ◽

...

Keyword(s):

Molecular Mechanisms ◽

Yeast Cells ◽

Meiotic Spindle ◽

Homologous Chromosomes ◽

Spindle Dynamics ◽

Live Cell Microscopy ◽

Spindle Stability ◽

Cell Microscopy ◽

Mitosis And Meiosis ◽

Meiosis I

ABSTRACTThe spindle apparatus segregates bi-oriented sister chromatids during mitosis but mono-oriented homologous chromosomes during meiosis I. It has remained unclear if similar molecular mechanisms operate to regulate spindle dynamics during mitosis and meiosis I. Here, we employed live-cell microscopy to compare the spindle dynamics of mitosis and meiosis I in fission yeast cells and demonstrated that the conserved kinesin-14 motor Klp2 plays a specific role in maintaining metaphase spindle length during meiosis I, but not during mitosis. Moreover, the maintenance of metaphase spindle stability during meiosis I requires the synergism between Klp2 and the conserved microtubule crosslinker Ase1 as the absence of both proteins causes exacerbated defects in metaphase spindle stability. The synergism is not necessary for regulating mitotic spindle dynamics. Hence, our work reveals a new molecular mechanism underlying meiotic spindle dynamics and provides insights into understanding differential regulation of meiotic and mitotic events.

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Nup132 modulates meiotic spindle attachment in fission yeast by regulating kinetochore assembly

The Journal of Cell Biology ◽

10.1083/jcb.201501035 ◽

2015 ◽

Vol 211 (2) ◽

pp. 295-308 ◽

Cited By ~ 8

Author(s):

Hui-Ju Yang ◽

Haruhiko Asakawa ◽

Tokuko Haraguchi ◽

Yasushi Hiraoka

Keyword(s):

Schizosaccharomyces Pombe ◽

Fission Yeast ◽

Meiotic Prophase ◽

Spindle Assembly Checkpoint ◽

Meiotic Spindle ◽

Spindle Attachment ◽

Kinetochore Assembly ◽

Sister Chromatids ◽

Monopolar Spindle ◽

Meiosis I

During meiosis, the kinetochore undergoes substantial reorganization to establish monopolar spindle attachment. In the fission yeast Schizosaccharomyces pombe, the KNL1–Spc7-Mis12-Nuf2 (KMN) complex, which constitutes the outer kinetochore, is disassembled during meiotic prophase and is reassembled before meiosis I. Here, we show that the nucleoporin Nup132 is required for timely assembly of the KMN proteins: In the absence of Nup132, Mis12 and Spc7 are precociously assembled at the centromeres during meiotic prophase. In contrast, Nuf2 shows timely dissociation and reappearance at the meiotic centromeres. We further demonstrate that depletion of Nup132 activates the spindle assembly checkpoint in meiosis I, possibly because of the increased incidence of erroneous spindle attachment at sister chromatids. These results suggest that precocious assembly of the kinetochores leads to the meiosis I defects observed in the nup132-disrupted mutant. Thus, we propose that Nup132 plays an important role in establishing monopolar spindle attachment at meiosis I through outer kinetochore reorganization at meiotic prophase.

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Abstract P070: NEU3 Sialidase Overexpression Activates Cell Survival in Murine Skeletal Myoblasts C2C12 and Protects Them from Hypoxia

Circulation Research ◽

10.1161/res.109.suppl_1.ap070 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Luigi Anastasia ◽

Raffaella Scaringi ◽

Nadia Papini ◽

Andrea Garatti ◽

Lorenzo Menicanti ◽

...

Keyword(s):

Skeletal Muscle ◽

Egf Receptor ◽

Day Treatment ◽

Horse Serum ◽

Critical Role ◽

Cell Loss ◽

Myoblast Differentiation ◽

Signalling Pathways ◽

Skeletal Myoblasts ◽

Culturing Conditions

Membrane-bound sialidase NEU3 increase during skeletal muscle differentiation has been shown to protect myoblasts from apoptosis and drive the differentiation process [1]. Thus, the objective of this study was to assess whether up-regulation of NEU3 would enhance the ability of murine skeletal muscle cells to resist to hypoxia, ultimately opposing cell death. We found that C2C12 myoblasts overexpressing NEU3 (L-NEU3) became highly resistant to 1% oxygen or 200 mM deferoxamine induced hypoxia. Moreover, L-NEU3 myoblasts survived a seven-day treatment of combined hypoxia and low serum (2% horse serum used to induce myoblast differentiation), without any significant cell loss. On the contrary, wild type C2C12 could not resist to these culturing conditions and all died within 48h. Real Time PCR showed NEU3 expression increase during all hypoxic treatments both in C2C12 and L-NEU3 cells, suggesting an endogenous NEU3 activation under these conditions. Moreover, we found that NEU3 over-expression activated pro-survival signalling pathways through up-regulation and activation of EGF receptor. Overall, our data support the hypothesis that NEU3 may play a critical role in the response of skeletal myoblasts to hypoxia and the preservation of cell viability by activating pro-survival signalling pathways. [1] Anastasia L. et al. J.Biol.Chem. 2008, 283 (52): 36265–36271.

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