scholarly journals Critical Role of the Epithelial Ca2+ Channel TRPV5 in Active Ca2+ Reabsorption as Revealed by TRPV5/Calbindin-D28K Knockout Mice

2006 ◽  
Vol 17 (11) ◽  
pp. 3020-3027 ◽  
Author(s):  
Dimitra Gkika ◽  
Yu-Juei Hsu ◽  
Annemiete W. van der Kemp ◽  
Sylvia Christakos ◽  
René J. Bindels ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Critical Role ◽  
Calbindin D28k

scholarly journals Regulation of the cognitive aging process by the transcriptional repressor RP58

2021 ◽  
Author(s):  
Tomoko Tanaka ◽  
Shinobu Hirai ◽  
Hiroyuki Manabe ◽  
Kentaro Endo ◽  
Hiroko Shimbo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Knockout Mice ◽  
Cognitive Aging ◽  
Critical Role ◽  
Harmful Effect ◽  
Transcriptional Repressor ◽  
Repair Pathway ◽  
Wild Type

Aging involves a decline in physiology which is a natural event in all living organisms. An accumulation of DNA damage contributes to the progression of aging. DNA is continually damaged by exogenous sources and endogenous sources. If the DNA repair pathway operates normally, DNA damage is not life threatening. However, impairments of the DNA repair pathway may result in an accumulation of DNA damage, which has a harmful effect on health and causes an onset of pathology. RP58, a zinc-finger transcriptional repressor, plays a critical role in cerebral cortex formation. Recently, it has been reported that the expression level of RP58 decreases in the aged human cortex. Furthermore, the role of RP58 in DNA damage is inferred by the involvement of DNMT3, which acts as a co-repressor for RP58, in DNA damage. Therefore, RP58 may play a crucial role in the DNA damage associated with aging. In the present study, we investigated the role of RP58 in aging. We used RP58 hetero-knockout and wild-type mice in adolescence, adulthood, or old age. We performed immunohistochemistry to determine whether microglia and DNA damage markers responded to the decline in RP58 levels. Furthermore, we performed an object location test to measure cognitive function, which decline with age. We found that the wild-type mice showed an increase in single-stranded DNA and gamma-H2AX foci. These results indicate an increase in DNA damage or dysfunction of DNA repair mechanisms in the hippocampus as age-related changes. Furthermore, we found that, with advancing age, both the wild-type and hetero-knockout mice showed an impairment of spatial memory for the object and increase in reactive microglia in the hippocampus. However, the RP58 hetero-knockout mice showed these symptoms earlier than the wild-type mice did. These results suggest that a decline in RP58 level may lead to the progression of aging.

scholarly journals Critical role of spectrin in hearing development and deafness

2019 ◽  
Vol 5 (4) ◽  
pp. eaav7803 ◽  
Author(s):  
Yan Liu ◽  
Jieyu Qi ◽  
Xin Chen ◽  
Mingliang Tang ◽  
Cenfeng Chu ◽  
...  
Keyword(s):  
Hair Cells ◽  
Knockout Mice ◽  
Crucial Role ◽  
Structural Organization ◽  
Critical Role ◽  
Super Resolution ◽  
Mechanical Vibrations ◽  
Hearing Ability ◽  
Profound Deafness

Inner ear hair cells (HCs) detect sound through the deflection of mechanosensory stereocilia. Stereocilia are inserted into the cuticular plate of HCs by parallel actin rootlets, where they convert sound-induced mechanical vibrations into electrical signals. The molecules that support these rootlets and enable them to withstand constant mechanical stresses underpin our ability to hear. However, the structures of these molecules have remained unknown. We hypothesized that αII- and βII-spectrin subunits fulfill this role, and investigated their structural organization in rodent HCs. Using super-resolution fluorescence imaging, we found that spectrin formed ring-like structures around the base of stereocilia rootlets. These spectrin rings were associated with the hearing ability of mice. Further, HC-specific, βII-spectrin knockout mice displayed profound deafness. Overall, our work has identified and characterized structures of spectrin that play a crucial role in mammalian hearing development.

scholarly journals Disruption of CXCR6 Ameliorates Kidney Inflammation and Fibrosis in Deoxycorticosterone Acetate/Salt Hypertension

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuanbo Wu ◽  
Changlong An ◽  
Xiaogao Jin ◽  
Zhaoyong Hu ◽  
Yanlin Wang
Keyword(s):  
Knockout Mice ◽  
Critical Role ◽  
Kidney Injury ◽  
Wild Type ◽  
Salt Treatment ◽  
Hypertensive Nephropathy ◽  
Deoxycorticosterone Acetate ◽  
Kidney Fibrosis ◽  
Salt Hypertension

AbstractCirculating cells have a pathogenic role in the development of hypertensive nephropathy. However, how these cells infiltrate into the kidney are not fully elucidated. In this study, we investigated the role of CXCR6 in deoxycorticosterone acetate (DOCA)/salt-induced inflammation and fibrosis of the kidney. Following uninephrectomy, wild-type and CXCR6 knockout mice were treated with DOCA/salt for 3 weeks. Blood pressure was similar between wild-type and CXCR6 knockout mice at baseline and after treatment with DOCA/salt. Wild-type mice develop significant kidney injury, proteinuria, and kidney fibrosis after three weeks of DOCA/salt treatment. CXCR6 deficiency ameliorated kidney injury, proteinuria, and kidney fibrosis following treatment with DOCA/salt. Moreover, CXCR6 deficiency inhibited accumulation of bone marrow–derived fibroblasts and myofibroblasts in the kidney following treatment with DOCA/salt. Furthermore, CXCR6 deficiency markedly reduced the number of macrophages and T cells in the kidney after DOCA/salt treatment. In summary, our results identify a critical role of CXCR6 in the development of inflammation and fibrosis of the kidney in salt-sensitive hypertension.

Abstract 319: Role of Phosphodiesterases 4B and 4D in cAMP Signal Compartmentation Around Calcium Handling Proteins

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Axel E Kraft ◽  
Viacheslav O Nikolaev ◽  
Marco Conti
Keyword(s):  
Knockout Mice ◽  
Heart Function ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Specific Effect ◽  
Resonance Energy ◽  
Direct Analysis ◽  
Calcium Handling ◽  
Camp Signaling

Phosphodiesterase subfamilies 4B and 4D are critically involved in the regulation of cAMP signaling in mammalian cardiomyocytes. Alterations in activity of these enzymes in human hearts have been shown to result in arrhythmia and heart failure. The aim of this project was to systematically investigate specific roles of PDE4B and PDE4D in regulating cAMP dynamics in three distinct subcellular microdomains formed around Ca 2+ handling proteins, such as L-type calcium channels (LTCCs), sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) and ryanodine receptors (RyRs), to understand their impact on heart function and disease. Transgenic mice expressing three different Förster resonance energy transfer (FRET) based cAMP biosensors targeted to caveolin rich plasma membrane, SERCA and RyR microdomains, were crossed with PDE4B and PDE4D knockout mice. Using FRET imaging in ventricular cardiomyocytes freshly isolated from wildtype and knockout mice, direct analysis of the specific effect of both PDE subfamilies in these microdomains could be performed by measuring the kinetics of local cAMP degradation. Our results indicate that the cAMP kinetics around the LTCC microdomain is critically regulated by PDE4B and PDE4D. So far was it has been known that the isoform that is associated with the RyR microdomain belongs to the PDE4D family, however we found PDE4B to be involved in regulating the cAMP signaling in this microdomain. PDE4D deletion also revealed the critical role of this subfamily for the control of cAMP dynamics in the SERCA microdomain of adult mouse cardiomyocytes. Basal levels of cAMP were elevated when PDE4B was absent from any of the PDE4B-regulated microdomain, whereas no such alterations were detected for PDE4D knockout cells. These data demonstrate that all three microdomains are differentially regulated by PDEs. Even within one organelle such as sarcoplasmic reticulum, we could show the existence of at least two distinct cAMP microdomains, i.e. around RyR and SERCA which are preferentially controlled by PDE4B and PDE4D, respectively. In the future, we aim to systematically analyze biochemical composition of the three microdomains, their distinct roles in cardiac function and disease as well as ways of their pharmacological modulation.

scholarly journals The Type 1 Insulin-Like Growth Factor Receptor (IGF-IR) Pathway Is Mandatory for the Follistatin-Induced Skeletal Muscle Hypertrophy

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 241-253 ◽  
Author(s):  
S. Kalista ◽  
O. Schakman ◽  
H. Gilson ◽  
P. Lause ◽  
B. Demeulder ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Knockout Mice ◽  
Muscle Hypertrophy ◽  
Critical Role ◽  
Muscle Growth ◽  
Dominant Negative ◽  
Wild Type ◽  
Myostatin Inhibition

Myostatin inhibition by follistatin (FS) offers a new approach for muscle mass enhancement. The aim of the present study was to characterize the mediators responsible for the FS hypertrophic action on skeletal muscle in male mice. Because IGF-I and IGF-II, two crucial skeletal muscle growth factors, are induced by myostatin inhibition, we assessed their role in FS action. First, we tested whether type 1 IGF receptor (IGF-IR) is required for FS-induced hypertrophy. By using mice expressing a dominant-negative IGF-IR in skeletal muscle, we showed that IGF-IR inhibition blunted by 63% fiber hypertrophy caused by FS. Second, we showed that FS caused the same degree of fiber hypertrophy in wild-type and IGF-II knockout mice. We then tested the role of the signaling molecules stimulated by IGF-IR, in particular the Akt/mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (S6K) pathway. We investigated whether Akt phosphorylation is required for the FS action. By cotransfecting a dominant-negative form of Akt together with FS, we showed that Akt inhibition reduced by 65% fiber hypertrophy caused by FS. Second, we evaluated the role of mTOR in FS action. Fiber hypertrophy induced by FS was reduced by 36% in rapamycin-treated mice. Finally, because the activity of S6K is increased by FS, we tested its role in FS action. FS caused the same degree of fiber hypertrophy in wild-type and S6K1/2 knockout mice. In conclusion, the IGF-IR/Akt/mTOR pathway plays a critical role in FS-induced muscle hypertrophy. In contrast, induction of IGF-II expression and S6K activity by FS are not required for the hypertrophic action of FS.

Human X chromosome exome sequencing identifies BCORL1 as contributor to spermatogenesis

2020 ◽  
Vol 58 (1) ◽  
pp. 56-65
Author(s):  
Chuncheng Lu ◽  
Yan Zhang ◽  
Yufeng Qin ◽  
Qiaoqiao Xu ◽  
Ran Zhou ◽  
...  
Keyword(s):  
Male Infertility ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
X Chromosome ◽  
Knockout Mice ◽  
Expression Patterns ◽  
Critical Role ◽  
Obstructive Azoospermia ◽  
Independent Population

BackgroundInfertility affects approximately 15% of couples worldwide with male infertility being responsible for approximately 50% of cases. Although accumulating evidence demonstrates the critical role of the X chromosome in spermatogenesis during the last few decades, the expression patterns and potential impact of the X chromosome, together with X linked genes, on male infertility are less well understood.MethodsWe performed X chromosome exome sequencing followed by a two-stage independent population validation in 1333 non-obstructive azoospermia cases and 1141 healthy controls to identify variant classes with high likelihood of pathogenicity. To explore the functions of these candidate genes in spermatogenesis, we first knocked down these candidate genes individually in mouse spermatogonial stem cells (SSCs) using short interfering RNA oligonucleotides and then generated candidate genes knockout mice by CRISPR-Cas9 system.ResultsFour low-frequency variants were identified in four genes (BCORL1, MAP7D3, ARMCX4 and H2BFWT) associated with male infertility. Functional studies of the mouse SSCs revealed that knocking down Bcorl1 or Mtap7d3 could inhibit SSCs self-renewal and knocking down Armcx4 could repress SSCs differentiation in vitro. Using CRISPR-Cas9 system, Bcorl1 and Mtap7d3 knockout mice were generated. Excitingly, Bcorl1 knockout mice were infertile with impaired spermatogenesis. Moreover, Bcorl1 knockout mice exhibited impaired sperm motility and sperm cells displayed abnormal mitochondrial structure.ConclusionOur data indicate that the X-linked genes are associated with male infertility and involved in regulating SSCs, which provides a new insight into the role of X-linked genes in spermatogenesis.

Evidence for a critical role of ceruloplasmin oxidase activity in iron metabolism of Wilson disease gene knockout mice

2010 ◽  
Vol 25 (6) ◽  
pp. 1144-1150 ◽  
Author(s):  
Uta Merle ◽  
Sabine Tuma ◽  
Thomas Herrmann ◽  
Valer Muntean ◽  
Martin Volkmann ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Knockout Mice ◽  
Wilson Disease ◽  
Oxidase Activity ◽  
Disease Gene ◽  
Gene Knockout ◽  
Critical Role ◽  
Gene Knockout Mice

scholarly journals PICK1 is essential for insulin production and the maintenance of glucose homeostasis

2018 ◽  
Vol 29 (5) ◽  
pp. 587-596 ◽  
Author(s):  
Jia Li ◽  
Zhuo Mao ◽  
Jiandong Huang ◽  
Jun Xia
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Knockout Mice ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Critical Role ◽  
Insulin Deficiency ◽  
Granule Formation ◽  
Proinsulin Processing

Protein interacting with C-kinase 1 (PICK1) is a peripheral membrane protein that controls insulin granule formation, trafficking, and maturation in INS-1E cells. However, global Pick1-knockout mice showed only a subtle diabetes-like phenotype. This raises the possibility that compensatory effects from tissues other than pancreatic beta cells may obscure the effects of insulin deficiency. To explore the role of PICK1 in pancreatic islets, we generated mice harboring a conditional Pick1 allele in a C57BL/6J background. The conditional Pick1-knockout mice exhibited impaired glucose tolerance, profound insulin deficiency, and hyperglycemia. In vitro experiments showed that the ablation of Pick1 in pancreatic beta cells selectively decreased the initial rapid release of insulin and the total insulin levels in the islets. Importantly, the specific ablation of Pick1 induced elevated proinsulin levels in the circulation and in the islets, accompanied by a reduction in the proinsulin processing enzymes prohormone convertase 1/3 (PC1/3). The deletion of Pick1 triggered the specific elimination of chromogranin B in pancreatic beta cells, which is believed to control granule formation and release. Collectively, these data demonstrate the critical role of PICK1 in secretory granule biogenesis, proinsulin processing, and beta cell function. We conclude that the beta cell–specific deletion of Pick1 in mice led to hyperglycemia and eventually to diabetes.

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