scholarly journals IFT-A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease

2020 ◽  
Author(s):  
Wei Wang ◽  
Tana S Pottorf ◽  
Henry H Wang ◽  
Ruochen Dong ◽  
Matthew A. Kavanaugh ◽  
...  
Keyword(s):  
Liver Disease ◽  
Notch Signaling ◽  
Primary Cilia ◽  
Intraflagellar Transport ◽  
Erk Signaling ◽  
Knock Out ◽  
Adult Mice ◽  
Autosomal Dominant Polycystic Kidney ◽  
Knock Out Mice ◽  
Cyst Lining

AbstractPolycystic liver disease (PLD) is characterized by the growth of numerous biliary cysts and presents in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD), causing significant morbidity. Interestingly, deletion of intraflagellar transport-B (IFT-B) genes in adult mouse models of ADPKD attenuates severity of PKD and PLD. Here we examine the role of deletion of IFT-A gene, Thm1, in PLD of juvenile and adult Pkd2 conditional knock-out mice. Perinatal deletion of Thm1 results in disorganized and expanded biliary regions, biliary fibrosis, shortened primary cilia on CK19+ biliary epithelial cells, and reduced Notch signaling. In contrast, perinatal deletion of Pkd2 causes PLD, with multiple CK19+ biliary epithelial cell-lined cysts, fibrosis, lengthened primary cilia, and increased Notch and ERK signaling. Perinatal deletion of Thm1 in Pkd2 conditional knock-out mice increased hepatomegaly and liver necrosis, indicating enhanced liver disease severity. In contrast to effects in the developing liver, deletion of Thm1 in adult mice, alone and together with Pkd2, did not cause a biliary phenotype nor affect Pkd2-mutant PLD, respectively. However, similar to juvenile PLD, Notch and ERK signaling were increased in adult Pkd2-mutant cyst-lining cholangiocytes. Taken together, Thm1 is required for biliary tract development, likely by enabling Notch signaling, and proper biliary development restricts PLD severity. Unlike IFT-B genes, Thm1 does not affect hepatic cystogenesis, suggesting divergent regulation of signaling and cystogenic processes in the liver by IFT-B and –A. Notably, increased Notch signaling in cyst-lining cholangiocytes may indicate that aberrant activation of this pathway promotes hepatic cystogenesis, presenting as a novel potential therapeutic target.

scholarly journals The Role of IFT140 in Osteogenesis of Adult Mice Long Bone

2019 ◽  
Vol 67 (8) ◽  
pp. 601-611 ◽  
Author(s):  
Dike Tao ◽  
Hui Xue ◽  
Chenyang Zhang ◽  
Gongchen Li ◽  
Yao Sun
Keyword(s):  
Primary Cilia ◽  
Core Protein ◽  
Bone Development ◽  
Intraflagellar Transport ◽  
Long Bone ◽  
Mineral Apposition Rate ◽  
Knock Out ◽  
Adult Mice ◽  
Knock Out Mice

Primary cilia have a pivotal role in bone development and the dysfunctions of primary cilia cause skeletal ciliopathies. Intraflagellar transport (IFT) proteins are conserved mediators of cilium signaling. IFT sub-complex A is known to regulate retrograde IFT in the cilium. As a core protein of IFT complex A, IFT140 has been shown to have a relationship with serious skeletal ciliopathies caused in humans. However, the effects and mechanisms of IFT140 in bone formation have not been systematically disclosed. To further investigate the potential role of IFT140 in osteogenesis, we established a mouse model by conditional deletion of IFT140 in pre-osteoblasts. The adult knock-out mice exhibited dwarf phenotypes, such as short bone length, less bone mass, and decreased bone mineral apposition rate. In addition, by IFT140 deletion, the expressions of several osteoblastic markers were decreased and loss of bone became severe with aging. These results suggest that cilia gene Ift140 is essential in bone development.

scholarly journals Lack of WWC2 Protein Leads to Aberrant Angiogenesis in Postnatal Mice

2021 ◽  
Vol 22 (10) ◽  
pp. 5321
Author(s):  
Viktoria Constanze Brücher ◽  
Charlotte Egbring ◽  
Tanja Plagemann ◽  
Pavel I. Nedvetsky ◽  
Verena Höffken ◽  
...  
Keyword(s):  
Signalling Pathway ◽  
Control Group ◽  
Knock Out ◽  
Ocular Angiogenesis ◽  
Sprouting Angiogenesis ◽  
Adult Mice ◽  
Upstream Regulator ◽  
Knock Out Mice ◽  
Hippo Signalling

The WWC protein family is an upstream regulator of the Hippo signalling pathway that is involved in many cellular processes. We examined the effect of an endothelium-specific WWC1 and/or WWC2 knock-out on ocular angiogenesis. Knock-outs were induced in C57BL/6 mice at the age of one day (P1) and evaluated at P6 (postnatal mice) or induced at the age of five weeks and evaluated at three months of age (adult mice). We analysed morphology of retinal vasculature in retinal flat mounts. In addition, in vivo imaging and functional testing by electroretinography were performed in adult mice. Adult WWC1/2 double knock-out mice differed neither functionally nor morphologically from the control group. In contrast, the retinas of the postnatal WWC knock-out mice showed a hyperproliferative phenotype with significantly enlarged areas of sprouting angiogenesis and a higher number of tip cells. The branching and end points in the peripheral plexus were significantly increased compared to the control group. The deletion of the WWC2 gene was decisive for these effects; while knocking out WWC1 showed no significant differences. The results hint strongly that WWC2 is an essential regulator of ocular angiogenesis in mice. As an activator of the Hippo signalling pathway, it prevents excessive proliferation during physiological angiogenesis. In adult animals, WWC proteins do not seem to be important for the maintenance of the mature vascular plexus.

scholarly journals Development of the cochlea in the absence of all Notch signaling: A study of O-fucosyltransferase conditional knock out mice

2006 ◽  
Vol 295 (1) ◽  
pp. 408
Author(s):  
Martin L. Basch ◽  
Takahiro Ohyama ◽  
Pamela Stanley ◽  
Andrew K. Groves ◽  
Neil Segil
Keyword(s):  
Notch Signaling ◽  
Knock Out ◽  
Knock Out Mice

scholarly journals LDL Receptor Knock-Out Mice Are a Physiological Model Particularly Vulnerable to Study the Onset of Inflammation in Non-Alcoholic Fatty Liver Disease

PLoS ONE ◽  
2012 ◽  
Vol 7 (1) ◽  
pp. e30668 ◽  
Author(s):  
Veerle Bieghs ◽  
Patrick J. Van Gorp ◽  
Kristiaan Wouters ◽  
Tim Hendrikx ◽  
Marion J. Gijbels ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Ldl Receptor ◽  
Physiological Model ◽  
Alcoholic Fatty Liver ◽  
Knock Out ◽  
Knock Out Mice ◽  
Alcoholic Fatty Liver Disease

Placental HTRA1 cleaves alpha-1-antitrypsin to generate a NET-Inhibitory Peptide

Blood ◽  
2021 ◽  
Author(s):  
Robert A. Campbell ◽  
Heather D Campbell ◽  
Joseph Samuel Bircher ◽  
Claudia Valeria de Araujo ◽  
Frederik Denorme ◽  
...  
Keyword(s):  
Serine Protease ◽  
Inhibitory Peptide ◽  
Littermate Control ◽  
Knock Out ◽  
Inhibitory Peptides ◽  
Adult Mice ◽  
Adult Plasma ◽  
Alpha 1 Antitrypsin ◽  
Knock Out Mice ◽  
Mouse Pup

Neutrophil extracellular traps (NETs) are important components of innate immunity. Neonatal neutrophils (PMNs) fail to form NETs due to circulating NET-Inhibitory Peptides (NIPs) -cleavage fragments of alpha-1-antitrypsin (A1AT). However, how fetal and neonatal blood NIPs are generated remains unknown. The placenta expresses High-Temperature Requirement serine protease A1 (HTRA1) during fetal development, which can cleave A1AT. We hypothesized that placentally expressed HTRA1 regulates the formation of NIPs and that NET competency changed in PMNs isolated from neonatal HTRA1-knock out mice (HTRA1-/-). We found that umbilical cord blood plasma has elevated HTRA1 levels compared to adult plasma, and that recombinant and placenta-eluted HTRA1 cleaves A1AT to generate an A1AT cleavage fragment (A1ATM383S-CF) of similar molecular weight to previously identified NIPs that block NET formation by adult neutrophils. We demonstrated that neonatal mouse pup plasma contains A1AT fragments which inhibit NET formation by PMNs isolated from adult mice, indicating that NIP generation during gestation is conserved across species. LPS-stimulated PMNs isolated from HTRA1+/+ littermate control pups exhibit delayed NET formation following birth. However, plasma from HTRA1-/- pups had no detectable NIPs and PMNs from HTRA1-/- pups became NET competent earlier after birth compared to HTRA1+/+ littermate controls. Finally, in the cecal slurry model of neonatal sepsis, A1ATM383S-CF improved survival in C57BL/6 pups by preventing pathogenic NET formation. Our data indicate that placentally expressed HTRA1 is a serine protease that cleaves A1AT in utero to generate NIPs that regulate NET formation by human and mouse PMNs.

scholarly journals The HSP90/R2TP assembly chaperone promotes cell proliferation in the intestinal epithelium

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chloé Maurizy ◽  
Claire Abeza ◽  
Bénédicte Lemmers ◽  
Monica Gabola ◽  
Ciro Longobardi ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Intestinal Epithelium ◽  
Core Component ◽  
Proliferating Cells ◽  
Knock Out ◽  
Differentiated Cells ◽  
Adult Mice ◽  
Cycle Arrest ◽  
Small Intestinal ◽  
Knock Out Mice

AbstractThe R2TP chaperone cooperates with HSP90 to integrate newly synthesized proteins into multi-subunit complexes, yet its role in tissue homeostasis is unknown. Here, we generated conditional, inducible knock-out mice for Rpap3 to inactivate this core component of R2TP in the intestinal epithelium. In adult mice, Rpap3 invalidation caused destruction of the small intestinal epithelium and death within 10 days. Levels of R2TP substrates decreased, with strong effects on mTOR, ATM and ATR. Proliferative stem cells and progenitors deficient for Rpap3 failed to import RNA polymerase II into the nucleus and they induced p53, cell cycle arrest and apoptosis. Post-mitotic, differentiated cells did not display these alterations, suggesting that R2TP clients are preferentially built in actively proliferating cells. In addition, high RPAP3 levels in colorectal tumors from patients correlate with bad prognosis. Here, we show that, in the intestine, the R2TP chaperone plays essential roles in normal and tumoral proliferation.

scholarly journals NaV1.2 haploinsufficiency in Scn2a knock-out mice causes an autistic-like phenotype attenuated with age

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Isabelle Léna ◽  
Massimo Mantegazza
Keyword(s):  
Wide Spectrum ◽  
Autism Spectrum ◽  
Face Validity ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Knock Out ◽  
Adult Mice ◽  
Ohtahara Syndrome ◽  
Knock Out Mice ◽  
Adolescent Period

Abstract Mutations of the SCN2A gene, encoding the voltage gated sodium channel NaV1.2, have been associated to a wide spectrum of epileptic disorders ranging from benign familial neonatal-infantile seizures to early onset epileptic encephalopathies such as Ohtahara syndrome. These phenotypes may be caused by either gain-of-function or loss-of-function mutations. More recently, loss-of-function SCN2A mutations have also been identified in patients with autism spectrum disorder (ASD) without overt epileptic phenotypes. Heterozygous Scn2a knock-out mice (Scn2a+/−) may be a model of this phenotype. Because ASD develops in childhood, we performed a detailed behavioral characterization of Scn2a+/− mice comparing the juvenile/adolescent period of development and adulthood. We used tasks relevant to ASD and the different comorbidities frequently found in this disorder, such as anxiety or intellectual disability. Our data demonstrate that young Scn2a+/− mice display autistic-like phenotype associated to impaired memory and reduced reactivity to stressful stimuli. Interestingly, these dysfunctions are attenuated with age since adult mice show only communicative deficits. Considering the clinical data available on patients with loss-of-function SCN2A mutations, our results indicate that Scn2a+/− mice constitute an ASD model with construct and face validity during the juvenile/adolescent period of development. However, more information about the clinical features of adult carriers of SCN2A mutations is needed to evaluate comparatively the phenotype of adult Scn2a+/− mice.

scholarly journals Intraflagellar transport-A deficiency attenuates ADPKD in a renal tubular- and maturation-dependent manner

2020 ◽  
Author(s):  
Wei Wang ◽  
Luciane M. Silva ◽  
Henry H. Wang ◽  
Matthew A. Kavanaugh ◽  
Tana S. Pottorf ◽  
...  
Keyword(s):  
Mouse Models ◽  
Primary Cilia ◽  
Protein Complexes ◽  
Collecting Duct ◽  
Intraflagellar Transport ◽  
Renal Tubules ◽  
Dependent Manner ◽  
Cortical Collecting Duct ◽  
Knock Out

AbstractPrimary cilia are sensory organelles that are built and maintained by intraflagellar transport (IFT) multi-protein complexes. Deletion of certain ciliary genes in Autosomal Dominant Polycystic Kidney Disease (ADPKD) mouse models markedly attenuates PKD severity, indicating that a component of cilia dysfunction may have potential therapeutic value. To broaden the role of ciliary dysfunction, here we investigate the role of global deletion of Ift-A gene, Thm1, in juvenile and adult ADPKD mouse models. In cyst-lining cells of both juvenile and adult ADPKD models, cortical collecting duct cilia lengths and cytoplasmic and nuclear levels of the nutrient sensor, O-linked β-Nacetylglucosamine (O-GlcNAc) were increased. Relative to juvenile Pkd2 conditional knock-out mice, deletion of Thm1 together with Pkd2 both increased and reduced cystogenesis in a tubule-specific manner without altering kidney function, inflammation, cilia lengths, and ERK, STAT3 and OGlcNAc signaling. In contrast, Thm1 deletion in adult ADPKD mouse models markedly attenuated almost all features of PKD, including renal cystogenesis, inflammation, cilia lengths, and ERK, STAT3 and O-GlcNAc signaling. These data suggest that differential factors in the microenvironments between renal tubules and between developing and mature kidneys influence cilia and ADPKD pathobiology. Further, since O-GlcNAcylation directly regulates ciliary homeostasis and the balance between glycolysis and oxidative phosphorylation, we propose that increased O-GlcNAcylation may promote certain key ADPKD pathological processes.

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