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101.
Functional dicer is necessary for appropriate specification of radial glia during early development of mouse telencephalon 总被引:1,自引:0,他引:1
Early telencephalic development involves transformation of neuroepithelial stem cells into radial glia, which are themselves neuronal progenitors, around the time when the tissue begins to generate postmitotic neurons. To achieve this transformation, radial precursors express a specific combination of proteins. We investigate the hypothesis that micro RNAs regulate the ability of the early telencephalic progenitors to establish radial glia. We ablate functional Dicer, which is required for the generation of mature micro RNAs, by conditionally mutating the Dicer1 gene in the early embryonic telencephalon and analyse the molecular specification of radial glia as well as their progeny, namely postmitotic neurons and basal progenitors. Conditional mutation of Dicer1 from the telencephalon at around embryonic day 8 does not prevent morphological development of radial glia, but their expression of Nestin, Sox9, and ErbB2 is abnormally low. The population of basal progenitors, which are generated by the radial glia, is disorganised and expanded in Dicer1-/- dorsal telencephalon. While the proportion of cells expressing markers of postmitotic neurons is unchanged, their laminar organisation in the telencephalic wall is disrupted suggesting a defect in radial glial guided migration. We found that the laminar disruption could not be accounted for by a reduction of the population of Cajal Retzius neurons. Together, our data suggest novel roles for micro RNAs during early development of progenitor cells in the embryonic telencephalon. 相似文献
102.
Leucocyte recruitment and molecular fortification of keratinocytes triggered by streptococcal M1 protein 下载免费PDF全文
Streptococcus pyogenes of the M1 serotype is commonly associated with invasive streptococcal infections and development of streptococcal toxic shock syndrome. The M1 protein is a powerful inducer of inflammatory responses for several human cell types, but the reason why M1 protein‐related strains is over‐represented in invasive streptococcal diseases is still not understood. This study was undertaken to investigate if soluble M1 protein can aggravate the severity of streptococcal skin infections in respect to inflammation, leucocyte recruitment, and tissue remodelling as seen in patients with cellulitis and necrotizing fasciitis. We found that HaCaT cells are able to recruit activated leucocytes when encountering M1 protein. Neither the bacterial protein nor activated leucocytes caused cell damage on HaCaT cells, instead HaCaT cells responded to the bacterial virulence factor by releasing several proteins protective against bacterial infection and leucocyte responses. However, although not cytotoxic, M1 protein completely abolished wound healing abilities of HaCaT cells. Taken together, our results demonstrate that M1 protein is a critical virulence factor that can augment streptococcal skin infection suggesting that the protein is an interesting target for drug development. 相似文献
103.
Differential toxicity of TAR DNA‐binding protein 43 isoforms depends on their submitochondrial localization in neuronal cells 下载免费PDF全文
Illari Salvatori Alberto Ferri Silvia Scaricamazza Ilaria Giovannelli Alessia Serrano Simona Rossi Nadia D'Ambrosi Mauro Cozzolino Andrea Di Giulio Sandra Moreno Cristiana Valle Maria Teresa Carrì 《Journal of neurochemistry》2018,146(5):585-597
104.
Sandra Berger-Müller Atsushi Sugie Fumio Takahashi Gaia Tavosanis Satoko Hakeda-Suzuki Takashi Suzuki 《PloS one》2013,8(12)
A hallmark of the central nervous system is its spatial and functional organization in synaptic layers. During neuronal development, axons form transient contacts with potential post-synaptic elements and establish synapses with appropriate partners at specific layers. These processes are regulated by synaptic cell-adhesion molecules. In the Drosophila visual system, R7 and R8 photoreceptor subtypes target distinct layers and form en passant pre-synaptic terminals at stereotypic loci of the axonal shaft. A leucine-rich repeat transmembrane protein, Capricious (Caps), is known to be selectively expressed in R8 axons and their recipient layer, which led to the attractive hypothesis that Caps mediates R8 synaptic specificity by homophilic adhesion. Contradicting this assumption, our results indicate that Caps does not have a prominent role in synaptic-layer targeting and synapse formation in Drosophila photoreceptors, and that the specific recognition of the R8 target layer does not involve Caps homophilic axon-target interactions. We generated flies that express a tagged synaptic marker to evaluate the presence and localization of synapses in R7 and R8 photoreceptors. These genetic tools were used to assess how the synaptic profile is affected when axons are forced to target abnormal layers by expressing axon guidance molecules. When R7 axons were mistargeted to the R8-recipient layer, R7s either maintained an R7-like synaptic profile or acquired a similar profile to r8s depending on the overexpressed protein. When R7 axons were redirected to a more superficial medulla layer, the number of presynaptic terminals was reduced. These results indicate that cell-surface molecules are able to dictate synapse loci by changing the axon terminal identity in a partially cell-autonomous manner, but that presynapse formation at specific sites also requires complex interactions between pre- and post-synaptic elements. 相似文献
105.
Edmond M. Linossi Indu R. Chandrashekaran Tatiana B. Kolesnik James M. Murphy Andrew I. Webb Tracy A. Willson Lukasz Kedzierski Alex N. Bullock Jeffrey J. Babon Raymond S. Norton Nicos A. Nicola Sandra E. Nicholson 《PloS one》2013,8(8)
Suppressor of Cytokine Signaling (SOCS)5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF) signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. We show for the first time that SOCS5 can interact directly with JAK via a unique, conserved region in its N-terminus, which we have termed the JAK interaction region (JIR). Co-expression of SOCS5 was able to specifically reduce JAK1 and JAK2 (but not JAK3 or TYK2) autophosphorylation and this function required both the conserved JIR and additional sequences within the long SOCS5 N-terminal region. We further demonstrate that SOCS5 can directly inhibit JAK1 kinase activity, although its mechanism of action appears distinct from that of SOCS1 and SOCS3. In addition, we identify phosphoTyr317 in Shc-1 as a high-affinity substrate for the SOCS5-SH2 domain and suggest that SOCS5 may negatively regulate EGF and growth factor-driven Shc-1 signaling by binding to this site. These findings suggest that different domains in SOCS5 contribute to two distinct mechanisms for regulation of cytokine and growth factor signaling. 相似文献
106.
Yann Cormerais Marina Pagnuzzi‐Boncompagni Sandra Schrtter Sandy Giuliano Eric Tambutt Hitoshi Endou Michael F. Wempe Gilles Pags Jacques Pouyssgur Vincent Picco 《Journal of cellular and molecular medicine》2019,23(4):2711-2718
Most cases of medulloblastoma (MB) occur in young children. While the overall survival rate can be relatively high, current treatments combining surgery, chemo‐ and radiotherapy are very destructive for patient development and quality of life. Moreover, aggressive forms and recurrences of MB cannot be controlled by classical therapies. Therefore, new therapeutic approaches yielding good efficacy and low toxicity for healthy tissues are required to improve patient outcome. Cancer cells sustain their proliferation by optimizing their nutrient uptake capacities. The L‐type amino acid transporter 1 (LAT1) is an essential amino acid carrier overexpressed in aggressive human cancers that was described as a potential therapeutic target. In this study, we investigated the therapeutic potential of JPH203, a LAT1‐specific pharmacological inhibitor, on two independent MB cell lines belonging to subgroups 3 (HD‐MB03) and Shh (DAOY). We show that while displaying low toxicity towards normal cerebral cells, JPH203 disrupts AA homeostasis, mTORC1 activity, proliferation and survival in MB cells. Moreover, we demonstrate that a long‐term treatment with JPH203 does not lead to resistance in MB cells. Therefore, this study suggests that targeting LAT1 with JPH203 is a promising therapeutic approach for MB treatment. 相似文献
107.
Ablation of PRC1 by small interfering RNA demonstrates that cytokinetic abscission requires a central spindle bundle in mammalian cells, whereas completion of furrowing does not 下载免费PDF全文
Mollinari C Kleman JP Saoudi Y Jablonski SA Perard J Yen TJ Margolis RL 《Molecular biology of the cell》2005,16(3):1043-1055
The temporal and spatial regulation of cytokinesis requires an interaction between the anaphase mitotic spindle and the cell cortex. However, the relative roles of the spindle asters or the central spindle bundle are not clear in mammalian cells. The central spindle normally serves as a platform to localize key regulators of cell cleavage, including passenger proteins. Using time-lapse and immunofluorescence analysis, we have addressed the consequences of eliminating the central spindle by ablation of PRC1, a microtubule bundling protein that is critical to the formation of the central spindle. Without a central spindle, the asters guide the equatorial cortical accumulation of anillin and actin, and of the passenger proteins, which organize into a subcortical ring in anaphase. Furrowing goes to completion, but abscission to create two daughter cells fails. We conclude the central spindle bundle is required for abscission but not for furrowing in mammalian cells. 相似文献
108.
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110.
Melissa Richard-Greenblatt Horacio Bach John Adamson Sandra Pe?a-Diaz Wu Li Adrie J. C. Steyn Yossef Av-Gay 《The Journal of biological chemistry》2015,290(38):23064-23076
Ergothioneine (EGT) is synthesized in mycobacteria, but limited knowledge exists regarding its synthesis, physiological role, and regulation. We have identified Rv3701c from Mycobacterium tuberculosis to encode for EgtD, a required histidine methyltransferase that catalyzes first biosynthesis step in EGT biosynthesis. EgtD was found to be phosphorylated by the serine/threonine protein kinase PknD. PknD phosphorylates EgtD both in vitro and in a cell-based system on Thr213. The phosphomimetic (T213E) but not the phosphoablative (T213A) mutant of EgtD failed to restore EGT synthesis in a ΔegtD mutant. The findings together with observed elevated levels of EGT in a pknD transposon mutant during in vitro growth suggests that EgtD phosphorylation by PknD negatively regulates EGT biosynthesis. We further showed that EGT is required in a nutrient-starved model of persistence and is needed for long term infection of murine macrophages. 相似文献