scholarly journals Loss of Ntrk2/Kiss1r Signaling in Oocytes Causes Premature Ovarian Failure

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 3098-3111 ◽  
Author(s):  
Mauricio D. Dorfman ◽  
Cecilia Garcia-Rudaz ◽  
Zefora Alderman ◽  
Bredford Kerr ◽  
Alejandro Lomniczi ◽  
...  
Keyword(s):  
Early Adulthood ◽  
Trophic Factors ◽  
Neural Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Survival Pathway ◽  
A Cell ◽  
Gonadotropin Surge ◽  
Communication Pathway ◽  
Periovulatory Follicles ◽  
Specific Deletion

Neurotrophins (NTs), once believed to be neural-specific trophic factors, are now known to also provide developmental cues to non-neural cells. In the ovary, NTs contribute to both the formation and development of follicles. Here we show that oocyte-specific deletion of the Ntrk2 gene that encodes the NTRK2 receptor (NTRK2) for neurotrophin-4/5 and brain-derived neurotrophic factor (BDNF) results in post-pubertal oocyte death, loss of follicular organization, and early adulthood infertility. Oocytes lacking NTRK2 do not respond to gonadotropins with activation of phosphatidylinositol 3-kinase (PI3K)-AKT-mediated signaling. Before puberty, oocytes only express a truncated NTRK2 form (NTRK2.T1), but at puberty full-length (NTRK2.FL) receptors are rapidly induced by the preovulatory gonadotropin surge. A cell line expressing both NTRK2.T1 and the kisspeptin receptor (KISS1R) responds to BDNF stimulation with activation of Ntrk2 expression only if kisspeptin is present. This suggests that BDNF and kisspeptin that are produced by granulosa cells (GCs) of periovulatory follicles act in concert to mediate the effect of gonadotropins on Ntrk2 expression in oocytes. In keeping with this finding, the oocytes of NTRK2-intact mice fail to respond to gonadotropins with increased Ntrk2 expression in the absence of KISS1R. Our results demonstrate that the preovulatory gonadotropin surge promotes oocyte survival at the onset of reproductive cyclicity by inducing oocyte expression of NTRK2.FL receptors that set in motion an AKT-mediated survival pathway. They also suggest that gonadotropins activate NTRK2.FL expression via a dual communication pathway involving BDNF and kisspeptin produced in GCs and their respective receptors NTRK2.T1 and KISS1R expressed in oocytes.

Targeting of mRNAs into Neuronal and Glial Processes: Intracellular and Extracellular Influences

1998 ◽  
Vol 4 (2) ◽  
pp. 77-87 ◽  
Author(s):  
Charles F. Landry ◽  
Anthony T. Campagnoni
Keyword(s):  
Trophic Factors ◽  
Cell Contact ◽  
Neural Cells ◽  
Number Of Factors ◽  
Multiple Processes ◽  
Transduction Mechanisms ◽  
A Cell ◽  
The Common ◽  
Mrna Targeting

Neurons and macroglia share the common, polarizing, morphological feature of multiple processes extending from a cell body, thereby defining two cellular domains. Frequently, specialized cellular activities occur within these processes, such as the dendrites of neurons and the myelin sheath of oligodendrocytes, which serve to define some of the functions of the cell. As a consequence, molecules involved in carrying out these functions need to be targeted to these domains, and mechanisms must exist for selecting and delivering these molecules to their appropriate locations. One mechanism that is emerging as increasingly important in targeting proteins to distal processes of neural cells is the translocation of the mRNAs encoding those proteins. In this review, we present many examples of such translocated mRNAs in neurons, astrocytes, and oligodendrocytes. There is a growing consensus that four major steps occur in mRNA targeting after transcription and exit of these molecules from the nucleus. These include 1) the assembly of mRNA into an RNA-protein granule, presumably around some translocation signal within the mRNA; 2) transport of the mRNA granule complex to distal sites via the cytoskeleton; 3) anchoring of the granule at the targeting site; and 4) translation of the localized mRNA to generate protein products in situ. It has become increasingly apparent that mRNA translocation is an active process, although many of the components of the translocation apparatus remain to be identified. Recent evidence also indicates that a number of factors can regulate the transport of mRNAs from within and without the cell. These include cell-cell contact, differentiation state, electrical activity, and trophic factors, which seem to exert their influence through signal transduction mechanisms that are only beginning to be defined. NEUROSCIENTIST 4:77-87, 1998

scholarly journals In B cells, phosphatidylinositol 5-phosphate 4-kinase–α synthesizes PI(4,5)P2 to impact mTORC2 and Akt signaling

2016 ◽  
Vol 113 (38) ◽  
pp. 10571-10576 ◽  
Author(s):  
Simon J. Bulley ◽  
Alaa Droubi ◽  
Jonathan H. Clarke ◽  
Karen E. Anderson ◽  
Len R. Stephens ◽  
...  
Keyword(s):  
Time Course ◽  
Mammalian Target Of Rapamycin ◽  
Underlying Mechanism ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Phosphorylation ◽  
Endogenous Protein ◽  
Lipid Kinases ◽  
A Cell ◽  
Genetic Deletion ◽  
Dt40 Cells

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are enigmatic lipid kinases with physiological functions that are incompletely understood, not the least because genetic deletion and cell transfection have led to contradictory data. Here, we used the genetic tractability of DT40 cells to create cell lines in which endogenous PI5P4Kα was removed, either stably by genetic deletion or transiently (within 1 h) by tagging the endogenous protein genomically with the auxin degron. In both cases, removal impacted Akt phosphorylation, and by leaving one PI5P4Kα allele present but mutating it to be kinase-dead or have PI4P 5-kinase activity, we show that all of the effects on Akt phosphorylation were dependent on the ability of PI5P4Kα to synthesize phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] rather than to remove PI5P. Although stable removal of PI5P4Kα resulted in a pronounced decrease in Akt phosphorylation at Thr308 and Ser473, in part because of reduced plasma membrane PIP3, its acute removal led to an increase in Akt phosphorylation only at Ser473. This process invokes activation primarily of mammalian target of rapamycin complex 2 (mTORC2), which was confirmed by increased phosphorylation of other mTORC2 substrates. These findings establish PI5P4Kα as a kinase that synthesizes a physiologically relevant pool of PI(4,5)P2 and as a regulator of mTORC2, and show a phenomenon similar to the “butterfly effect” described for phosphatidylinositol 3-kinase Iα [Hart JR, et al. (2015) Proc Natl Acad Sci USA 112(4):1131–1136], whereby through apparently the same underlying mechanism, the removal of a protein’s activity from a cell can have widely divergent effects depending on the time course of that removal.

Establishment of a cell-to-cell communication pathway between separate carpels during gynoecium development

Planta ◽  
1995 ◽  
Vol 195 (3) ◽  
pp. 450-455 ◽  
Author(s):  
Chris van der Schoot ◽  
Margaret A. Dietrich ◽  
Marc Storms ◽  
Judith A. Verbeke ◽  
William J. Lucas
Keyword(s):  
Cell Communication ◽  
A Cell ◽  
Communication Pathway ◽  
Gynoecium Development

scholarly journals Ubiquitin-Dependent Rapid Degradation Conceals A Cell-Protective Function of Cytoplasmic SIRT3 Against Oxidative Stress

2020 ◽  
Author(s):  
Takashi Hayashi ◽  
Takashi Matsushita ◽  
Shin Hisahara ◽  
Naotoshi Iwahara ◽  
Atsushi Kuno ◽  
...  
Keyword(s):  
Cell Death ◽  
Nuclear Translocation ◽  
Neural Precursor ◽  
Neural Cells ◽  
Protective Function ◽  
Lysine Residues ◽  
Dependent Protein ◽  
A Cell ◽  
Protein Deacetylase ◽  
Superoxide Dismutase 2

Abstract SIRT3 is a NAD+-dependent protein deacetylase localized in mitochondria. Although several previous studies reported cytoplasmic and/or nuclear localization of SIRT3, extra-mitochondrial SIRT3 was obscure. We found that mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs were expressed in the mouse brain and diffuse SIRT3 immunostaining in cytoplasm was detected in cultured neural cells and neural precursor cells where SIRT3 knockdown disturbed neural precursor cell differentiation. However, overexpression of SIRT3 in COS7 cells showed that expression levels of SIRT3ct was much lower than that of SIRT3mt. SIRT3ct but not SIRT3mt was promptly degraded by the ubiquitin-dependent degradation, in which SIRT3ct degradation was mediated mainly by the ubiquitination of NH2-terminal methionine and partly by that of lysine residues. SIRT3ct expression level was significantly enhanced by the treatment of cells with staurosporine or H2O2. H2O2 promoted nuclear translocation of SIRT3ct and induced histone H3 deacetylation and superoxide dismutase 2 expression. The overexpression of SIRT3ct decreased cell death by H2O2 at similar levels achieved by that of SIRT3mt. Knockdown of Sirt3 mRNA increased cell death by amyloid-b (Ab) and the overexpression of SIRT3ct opposed the toxic function of Ab in PC12 cells. These results indicated that SIRT3ct participated in cell survival under various stress conditions.

scholarly journals Depletion of adipocyte Becn1 leads to lipodystrophy and metabolic dysregulation

2020 ◽  
Author(s):  
Ada Admin ◽  
Young Jin ◽  
Yul Ji ◽  
Yaechan Song ◽  
Sung Sik Choe ◽  
...  
Keyword(s):  
Cell Death ◽  
Adipose Tissue ◽  
Er Stress ◽  
Metabolic Diseases ◽  
Class Iii ◽  
Phosphatidylinositol 3 Kinase ◽  
Metabolic Dysregulation ◽  
A Cell ◽  
Stress Gene

<i>Becn1</i>/Beclin-1<i> </i>is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although <i>Becn1</i> has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of <i>Becn1</i> in white adipose tissue and related metabolic diseases remains elusive. Here we show that adipocyte-specific <i>Becn1</i> knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, insulin resistance. Ablation of <i>Becn1</i> in adipocytes stimulates programmed cell death in a cell-autonomous manner, accompanied by elevated ER stress gene expression. Furthermore, we observed that <i>Becn1 </i>depletion sensitized mature adipocytes to ER stress, leading to accelerated cell death. Taken together, these data suggest that adipocyte <i>Becn1</i> would serve as a crucial player for adipocyte survival and adipose tissue homeostasis.

scholarly journals An essential cell-autonomous role for hepcidin in cardiac iron homeostasis

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Samira Lakhal-Littleton ◽  
Magda Wolna ◽  
Yu Jin Chung ◽  
Helen C Christian ◽  
Lisa C Heather ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Metabolic Dysfunction ◽  
Cardiac Iron ◽  
Cardiac Iron Overload ◽  
A Cell ◽  
The Brain ◽  
Specific Deletion

Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain.

scholarly journals Depletion of adipocyte Becn1 leads to lipodystrophy and metabolic dysregulation

2020 ◽  
Author(s):  
Ada Admin ◽  
Young Jin ◽  
Yul Ji ◽  
Yaechan Song ◽  
Sung Sik Choe ◽  
...  
Keyword(s):  
Cell Death ◽  
Adipose Tissue ◽  
Er Stress ◽  
Metabolic Diseases ◽  
Class Iii ◽  
Phosphatidylinositol 3 Kinase ◽  
Metabolic Dysregulation ◽  
A Cell ◽  
Stress Gene

<i>Becn1</i>/Beclin-1<i> </i>is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although <i>Becn1</i> has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of <i>Becn1</i> in white adipose tissue and related metabolic diseases remains elusive. Here we show that adipocyte-specific <i>Becn1</i> knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, insulin resistance. Ablation of <i>Becn1</i> in adipocytes stimulates programmed cell death in a cell-autonomous manner, accompanied by elevated ER stress gene expression. Furthermore, we observed that <i>Becn1 </i>depletion sensitized mature adipocytes to ER stress, leading to accelerated cell death. Taken together, these data suggest that adipocyte <i>Becn1</i> would serve as a crucial player for adipocyte survival and adipose tissue homeostasis.

Ordered Arrays of Type B Botulinum Toxin On Phospholipid Vesicles

1990 ◽  
Vol 48 (1) ◽  
pp. 496-497
Author(s):  
F. Schmid ◽  
B. R. DasGupta ◽  
J. P. Robinson
Keyword(s):  
Neural Cells ◽  
Disulfide Linkage ◽  
Cell Internalization ◽  
Infection Models ◽  
Botulinum Neurotoxins ◽  
A Cell ◽  
Single Polypeptide ◽  
Endogenous Proteases ◽  
Carboxy Terminal ◽  
Polypeptide Chains

Botulinum neurotoxins comprise a family of potent toxins produced by the bacterium Clostridium botulinum. There are seven serologically distinct types of botulinum neurotoxins and they act near the neuromuscular junction, producing a flaccid paralysis. These neurotoxins are synthesized as single polypeptide chains which may be cleaved artificially or by endogenous proteases to more active dichain forms which are covalently held by disulfide linkage. The carboxy terminal 2/3 of the molecule is designated the heavy (H) chain, the rest is referred to as the light (L) chain. The neurotoxins have a molecular weight of approximately 150kD (for general review, Simpson, 1986)Simpson (1986) has proposed, by analogy to other bacterial toxins and viral infection models that the mode of action of these toxins proceed in three stages: binding to the surface of a cell, internalization and an enzymatic action. These functions can be separated biochemically; for example, the chains bind to the the cell surface and internalize. The enzymatic activity probably involves the L chain. This enzymatic poisoning step in neural cells is not known.

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