scholarly journals SEX-SPECIFIC TRAJECTORIES OF REELIN-DEPENDENT MATURATION OF DEEP LAYER PREFRONTAL NEURONS

2021 ◽  
Author(s):  
Thenzing J Silva Hurtado ◽  
Olivier Lassalle ◽  
Antoine Ameloot ◽  
Pascale Chavis
Keyword(s):  
Matrix Protein ◽  
Pyramidal Neurons ◽  
Deep Layer ◽  
Long Term Potentiation ◽  
Developmental Trajectory ◽  
Extracellular Matrix Protein ◽  
Wild Type ◽  
Functional Maturation

Throughout early adulthood, the anatomical and functional maturation of PFC circuitry continues under the influence of multiple extrinsic and intrinsic factors, most notably electrical activity, and molecular cues. We previously showed that the extracellular matrix protein reelin orchestrates the structural and functional maturation of deep layers medial PFC (mPFC) pyramidal neurons. Additionally, we reported that reelin haploinsufficiency is associated to prefrontal disruptions of long-term memory retention thereby illustrating the eminent role of reelin in cognitive maturation of the PFC. Prefrontal maturation follows a sex-specific developmental pattern, supporting the existence of sexual differences in the morphology-functional properties PFC. Here, we interrogated the role of reelin in the functional maturation of excitatory networks in the mPFC. The developmental trajectory of reelin's expression and deep layer pyramidal neurons synaptic plasticity was tracked in the mPFC of male and female mice, from the juvenile period to adulthood. To assess the role of reelin in both sexes, wild-type and heterozygous reeler mice (HRM) were compared. The results show that the maturational profile of reelin expression in the mPFC is sex-dependent and that the developmental trajectory of long-term potentiation is different between wild-type males and females. These data demonstrate reelin influence on prefrontal synapses is sex and period specific.

Extracellular Matrix Protein Matrilin-4 Regulates HSC Stress Response

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 601-601
Author(s):  
Hannah Uckelmann ◽  
Sandra Blaszkiewicz ◽  
Marieke Essers
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Extracellular Matrix ◽  
Matrix Protein ◽  
Bone Marrow Cells ◽  
Blood System ◽  
Extracellular Matrix Protein

Abstract The life-long maintenance of the blood system is accomplished by a pool of self-renewing multipotent hematopoietic stem cells (HSCs). Adult HSCs are found in a dormant state for most of their lifetime, entering cell cycle only to maintain homeostatic blood supply. Under stress conditions such as infection or chemotherapy, the loss of mature blood cells leads to an activation of dormant HSCs to replenish the blood system. Gene expression analysis performed by our group now revealed that Matrilin-4 is highly expressed in long-term HSCs (LT-HSCs) compared to short-term HSCs or committed progenitors, suggesting a potential role of Matrilin-4 in HSC function. Matrilin-4 is a member of the von Willebrand factor A-containing family of extracellular adapter proteins, which form filamentous structures outside of cells. Using mice lacking the entire family of Matrilins (1-4) we have investigated the role of Matrilins in HSC function. Constitutive Matrilin 1-4 KO mice exhibit normal hematopoiesis with a mild reduction in bone marrow cellularity and LSK numbers. However, when Matrilin KO bone marrow cells are pushed to proliferate in competitive transplantation assays with wildtype (WT) cells, they show a striking growth advantage. In a competitive transplant setting, where bone marrow cells of Matrilin KO versus WT mice are transplanted in a 1:1 ratio, the KO cells outcompete WT cells within four weeks, reaching a 90% chimerism at 16 weeks. This competitive advantage of Matrilin KO cells is evident in the long-term stem cell level as well as progenitors and is consistent in secondary transplants. To explore this remarkable phenotype, we performed single cell transplantation experiments of LT-HSCs and observed a more rapid reconstitution of peripheral blood cell levels of KO HSCs compared to WT controls. Confirming this growth advantage, Matrilin KO LSK cells show higher colony forming and serial replating potential in vitro, which can be rescued by the addition of recombinant or overexpressed Matrilin-4. While Matrilin-4 is highly expressed in homeostatic HSCs, in vivo treatment with IFNα or other inflammatory agents, such as LPS or G-CSF result in a dramatic downregulation (25-fold) of Matrilin-4 on the transcript as well as the protein level. Moreover, Matrilin KO HSCs are more sensitive to inflammatory stress, as they show a 2-fold stronger cell cycle activation in response to IFNα in vivo. Critically, Matrilin-4 KO HSCs return to the G0 state of the cell cycle normally after stress-induced activation and transplantation, thereby preventing their exhaustion. In summary, we show that the extracellular matrix protein Matrilin-4 is a novel component of the HSC niche, regulating HSC stress response. Surprisingly, HSCs lacking this extracellular matrix protein show a higher HSC potential due to an accelerated response to stress. Our data suggest that high expression of Matrilin-4 in LT-HSCs confers a resistance to stress stimuli. In situations of acute stress such as infection or transplantation however, this protection is rapidly lost to allow HSCs to efficiently replenish the blood system. Disclosures No relevant conflicts of interest to declare.

Experimental Inhibition of Periostin Attenuates Kidney Fibrosis

2017 ◽  
Vol 46 (6) ◽  
pp. 501-517 ◽  
Author(s):  
Jin Ho Hwang ◽  
Seung Hee Yang ◽  
Yong Chul Kim ◽  
Jin Hyuk Kim ◽  
Jung Nam An ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Matrix Protein ◽  
Collecting Duct ◽  
Extracellular Matrix Protein ◽  
In Vitro Experiments ◽  
Wild Type ◽  
In The Wild ◽  
Renal Fibrogenesis

Background: Periostin is responsible for tissue regeneration, fibrosis, and wound healing via its interaction with integrin. Recently, the role of periostin has been shown to contribute to fibrosis in chronic kidney disease. We investigated the role of periostin and the effect of periostin blockade in renal fibrogenesis. Methods: We investigated the function of periostin in vivo in wild-type and periostin-null mice (Postn-KO) in a unilateral ureteral obstruction (UUO) model. For the in vitro experiments, primary cultured inner medullary collecting duct cells from the wild-type and Postn-KO mice were used. Results: Periostin expression was strongly induced by UUO in the wild-type mice. UUO induced renal fibrosis and morphological changes in the obstructed kidney of wild-type mice, whereas global knockout of periostin reduced fibrosis induced by UUO and improved kidney structure. Fibrosis- and inflammation-related mRNA were significantly induced in the wild-type mice and were decreased in the Postn-KO mice. Additionally, α-smooth muscle actin expression was increased following the administration of recombinant periostin in vitro. The effect of periostin blockade was examined using 2 methods. The integrin blockade peptide decreased fibrosis-related gene expression in in vitro experiments. Anti-periostin polyclonal antibody attenuated renal fibrosis induced by UUO through changes in transforming growth factor-β signaling and the inflammatory and apoptotic pathways. Conclusion: Periostin is a marker of renal fibrosis and may augment the progression of fibrogenesis as an extracellular matrix protein. Periostin blockade effectively attenuated renal fibrogenesis. Thus, periostin inhibition may be a therapeutic strategy for the amelioration of renal disease progression.

Abstract 291: Fibulin-1 is Required to Prevent Hypoplastic Semilunar Valve Formation

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Keerthi Harikrishnan ◽  
Marion A Cooley ◽  
Waleed O Twal ◽  
Victor M Fresco ◽  
Christine B Kern ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Pulmonary Valve ◽  
Extracellular Matrix Protein ◽  
Semilunar Valve ◽  
Anterior Leaflet ◽  
Wild Type ◽  
Endocardial Cushions ◽  
Cell Numbers ◽  
Valve Formation

Fibulin-1 (Fbln1), an extracellular matrix protein, is prominently expressed during outflow tract (OFT) morphogenesis as a component of both the endocardial cushions and OFT valves. Here we sought to investigate the role of Fbln1 in the process of OFT valvulogenesis. Since Fbln1 null mice die perinatally, we first evaluated the effects of Fbln1 deficiency on OFT valve morphology in hearts of embryos at E17.5. Morphometric analysis of 3D reconstructions revealed that in Fbln1 nulls the volume of the anterior leaflet of the pulmonary valve, and the left and non-coronary leaflets of the aortic valve were significantly reduced as compared to wild type (WT) (30-40% reduction; WT n=6, null n=8; p<0.05). The reduced leaflet size correlated with decreased leaflet cell numbers (45%, 30% and 30% respectively; p<0.05). TUNEL and BrdU analysis showed no difference between E17.5 WT and Fbln1 null OFT valves. To determine when abnormalities of OFT valve leaflet cell numbers first occurs, OFT endocardial cushions and prevalvular mesenchyme from E10.5-14.5 null and WT embryos were analyzed. At E10.5, the proximal OFT cushions of Fbln1 nulls were hypercellular (34% increase; p<0.05; n=5 for each genotype) whereas cellularity of distal cushions was not different from WT (p= 0.49). The fact that the ratio of proximal OFT cushion mesenchymal cells to endothelial cells was increased in E10.5 Fbln1 null cushions suggests that alteration in EMT might contribute to the hypercellularity. At E12.5, cellularity of the proximal OFT cushions was observed to decrease by 35% (p<0.05; WT n=4; null n=4). This was accompanied by a 172% increase in apoptosis, with no alteration in the level of proliferation (p<0.05; WT n=3; null n=4). Decreased cellularity and increased apoptosis persisted in the OFT prevalvular mesenchyme of Fbln1 nulls at E14.5 (p<0.05; WT n=2; null n=2). Taken together, Fbln1 specifically regulates cellularization of the proximal endocardial cushion and prevalvular mesenchyme. Mechanistically, Fbln1 may act as a suppressor of cushion EMT and indirectly or directly as an inhibitor of apoptosis.

scholarly journals Impaired long-term potentiation and long-term memory deficits in xCT-deficient sut mice

2012 ◽  
Vol 32 (3) ◽  
pp. 315-321 ◽  
Author(s):  
Yan Li ◽  
Zhibing Tan ◽  
Zhigang Li ◽  
Zhongsheng Sun ◽  
Shumin Duan ◽  
...  
Keyword(s):  
Long Term Potentiation ◽  
Long Term Memory ◽  
Wild Type ◽  
Neuronal Function ◽  
Extracellular Glutamate ◽  
Term Memory ◽  
Term Potentiation ◽  
Basal Synaptic Transmission

xCT is the functional subunit of the cystine/glutamate antiporter system xc−, which exchanges intracellular glutamate with extracellular cystine. xCT has been reported to play roles in the maintenance of intracellular redox and ambient extracellular glutamate, which may affect neuronal function. To assess a potential role of xCT in the mouse hippocampus, we performed fear conditioning and passive avoidance for long-term memories and examined hippocampal synaptic plasticity in wild-type mice and xCT-null mutants, sut mice. Long-term memory was impaired in sut mice. Normal basal synaptic transmission and short-term presynaptic plasticity at hippocampal Schaffer collateral–CA1 synapses were observed in sut mice. However, LTP (long-term potentiation) was significantly reduced in sut mice compared with their wild-type counterparts. Supplementation of extracellular glutamate did not reverse the reduction in LTP. Taken together, our results suggest that xCT plays a role in the modulation of hippocampal long-term plasticity.

The role of PKMζ in the maintenance of long-term memory: a review

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Hamish Patel ◽  
Reza Zamani
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Long Term Potentiation ◽  
Global Memory ◽  
Long Term Memory ◽  
Compensatory Mechanism ◽  
Term Memory ◽  
Kinase C

Abstract Long-term memories are thought to be stored in neurones and synapses that undergo physical changes, such as long-term potentiation (LTP), and these changes can be maintained for long periods of time. A candidate enzyme for the maintenance of LTP is protein kinase M zeta (PKMζ), a constitutively active protein kinase C isoform that is elevated during LTP and long-term memory maintenance. This paper reviews the evidence and controversies surrounding the role of PKMζ in the maintenance of long-term memory. PKMζ maintains synaptic potentiation by preventing AMPA receptor endocytosis and promoting stabilisation of dendritic spine growth. Inhibition of PKMζ, with zeta-inhibitory peptide (ZIP), can reverse LTP and impair established long-term memories. However, a deficit of memory retrieval cannot be ruled out. Furthermore, ZIP, and in high enough doses the control peptide scrambled ZIP, was recently shown to be neurotoxic, which may explain some of the effects of ZIP on memory impairment. PKMζ knockout mice show normal learning and memory. However, this is likely due to compensation by protein-kinase C iota/lambda (PKCι/λ), which is normally responsible for induction of LTP. It is not clear how, or if, this compensatory mechanism is activated under normal conditions. Future research should utilise inducible PKMζ knockdown in adult rodents to investigate whether PKMζ maintains memory in specific parts of the brain, or if it represents a global memory maintenance molecule. These insights may inform future therapeutic targets for disorders of memory loss.

scholarly journals Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing

2021 ◽  
Author(s):  
Sujeong Yang ◽  
Sylvain Gigout ◽  
Angelo Molinaro ◽  
Yuko Naito-Matsui ◽  
Sam Hilton ◽  
...  
Keyword(s):  
Chondroitin Sulphate ◽  
Memory Loss ◽  
Memory Deficits ◽  
Long Term Potentiation ◽  
Aged Mice ◽  
Age Related ◽  
Term Potentiation ◽  
Early Memory

AbstractPerineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.

Thrombospondin-4 knockout in hypertension protects small-artery endothelial function but induces aortic aneurysms

2016 ◽  
Vol 310 (11) ◽  
pp. H1486-H1493 ◽  
Author(s):  
Teresa Palao ◽  
Catarina Rippe ◽  
Henk van Veen ◽  
Ed VanBavel ◽  
Karl Swärd ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Matrix Protein ◽  
Pressure Overload ◽  
Aortic Aneurysms ◽  
Endoplasmic Reticulum Stress Response ◽  
Extracellular Matrix Protein ◽  
Ang Ii ◽  
Wild Type ◽  
Resistance Arteries ◽  
Thrombospondin 4

Thrombospondin-4 (TSP-4) is a multidomain calcium-binding protein that has both intracellular and extracellular functions. As an extracellular matrix protein, it is involved in remodeling processes. Previous work showed that, in the cardiovascular system, TSP-4 expression is induced in the heart in response to experimental pressure overload and infarction injury. Intracellularly, it mediates the endoplasmic reticulum stress response in the heart. In this study, we explored the role of TSP-4 in hypertension. For this purpose, wild-type and TSP-4 knockout ( Thbs4 −/−) mice were treated with angiotensin II (ANG II). Hearts from ANG II-treated Thbs4 −/− mice showed an exaggerated hypertrophic response. Interestingly, aortas from Thbs4 −/− mice treated with ANG II showed a high incidence of aneurysms. In resistance arteries, ANG II-treated wild-type mice showed impaired endothelial-dependent relaxation. This was not observed in ANG II-treated Thbs4 −/− mice or in untreated controls. No differences were found in the passive pressure-diameter curves or stress-strain relationships, although ANG II-treated Thbs4 −/− mice showed a tendency to be less stiff, associated with thicker diameters of the collagen fibers as revealed by electron microscopy. We conclude that TSP-4 plays a role in hypertension, affecting cardiac hypertrophy, aortic aneurysm formation, as well as endothelial-dependent relaxation in resistance arteries.

Sign in / Sign up

Export Citation Format

Share Document